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Wicker, L. S., B. J. Miller, P. A. Fischer, A. Pressey e L. B. Peterson. "Genetic control of diabetes and insulitis in the nonobese diabetic mouse. Pedigree analysis of a diabetic H-2nod/b heterozygote." Journal of Immunology 142, n.º 3 (1 de fevereiro de 1989): 781–84. http://dx.doi.org/10.4049/jimmunol.142.3.781.
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Abstract The development of autoimmune type 1 diabetes mellitus in man and the nonobese diabetic (NOD) mouse is greatly influenced by a gene linked to the MHC. Although homozygosity at the NOD MHC is required for a high prevalence of disease, during backcross studies we have found a small number of diabetic H-2nod/b MHC heterozygotes. These diabetic heterozygotes could either represent a crossover event between the MHC and a putative MHC-linked diabetogenic gene or, alternatively, they could indicate that there is a dominant MHC-linked diabetic gene that has low penetrance in the heterozygous state. Pedigree analysis of a diabetic H-2nod/b MHC heterozygote favors the latter hypothesis.
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Everse, Stephen J., Thomas Orfeo, Kathleen E. Brummel-Ziedins, Matthew F. Hockin e Kenneth G. Mann. "Predicting Thrombosis in Factor VLeiden Heterozygotes." Blood 112, n.º 11 (16 de novembro de 2008): 1818. http://dx.doi.org/10.1182/blood.v112.11.1818.1818.
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Abstract Factor VLeiden (G1691A;R506Q) is an autosomal dominant allele displaying high prevalence (3–7%) in the United States Caucasian population and a high incidence of venous thrombosis in homozygotes (50% lifetime risk) but reduced penetrance in heterozygote carriers (<10% lifetime risk). Factors that precipitate or suppress the expression of the thrombotic phenotype in factor VLeiden heterozygotes are not well defined except for relatively infrequent instances of coexpression of other thrombophilic risk factors, e.g. the prothrombin G20210A mutant. Our goal is to mathematically evaluate the effect of factor VLeiden on tissue factor-initiated thrombin generation and determine whether concentration variations within the normal range of antithrombin (86–128%), prothrombin (60–140%) or protein C (77–183%) modulate the factor VLeiden effect when all other factor levels are at mean physiologic concentrations. Our mathematical model (Hockin et al. (2002) JBC 277:18322) was extended to incorporate the protein C pathway by including descriptions of thrombin binding to thrombomodulin, activation of protein C and factor Va inactivation by activated protein C. Simulations were conducted with 100% factor V, 50% factor V/50% factor VLeiden (heterozygote), and 100% factor VLeiden (homozygote). Heterozygous expression of factor VLeiden increases the maximum level of thrombin by 25% and the maximum rate of thrombin generation by a factor of 1.6 over that seen with 100% factor V. Homozygous factor VLeiden yields a 2.6-fold increase in maximum rate and a 60% increase in maximum thrombin level compared to 100% factor V. Decreasing the protein C concentration to 77% in a factor VLeiden heterozygote results in a thrombin generation profile with maximum levels and rates comparable to the factor VLeiden homozygote. At 150% protein C, thrombin generation is suppressed to levels similar to those seen with 100% factor V. When the effect of variable prothrombin levels in a factor VLeiden heterozygote is examined, a 60% level of prothrombin decreases the maximum level of thrombin generation below that seen with 100% factor V. When prothrombin levels are at 140% in the factor VLeiden heterozygote, the thrombin generation profile is similar to that observed with 100% factor VLeiden . When the effect of variable antithrombin levels was tested in a factor VLeiden heterozygote, a 14% decrease in antithrombin resulted in maximum thrombin levels approaching those of the factor VLeiden homozygote. In contrast, 128% antithrombin in a factor VLeiden heterozygote resulted in the suppression of thrombin generation to levels consistent with those seen with 100% factor V. Our results predict that the thrombotic effect of heterogenous expression of factor VLeiden can be reduced when prothrombin levels are at the low extreme of the normal range or when antithrombin or protein C levels are at the high extreme of the normal range. Conversely, the thrombotic effect of the heterozygous expression of factor VLeiden is intensified when prothrombin levels are at the high extreme of normal values or when antithrombin or protein C levels at the low extreme of normal. These results may contribute to the understanding of phenotypic variation within factor VLeiden heterozygotes.
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Arora, Jatin, Federica Pierini, Paul J. McLaren, Mary Carrington, Jacques Fellay e Tobias L. Lenz. "HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation". Molecular Biology and Evolution 37, n.º 3 (22 de outubro de 2019): 639–50. http://dx.doi.org/10.1093/molbev/msz249.
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Abstract Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individual’s HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.
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Falchetti, Alberto, Annamaria Morelli, Andrea Amorosi, Francesco Tonelli, Silvia Fabiani, Valentina Martineti, Roberto Castello, Lino Furlani e Maria Luisa Brandi. "Allelic Loss in Parathyroid Tumors from Individuals Homozygous for Multiple Endocrine Neoplasia Type 11". Journal of Clinical Endocrinology & Metabolism 82, n.º 7 (1 de julho de 1997): 2278–82. http://dx.doi.org/10.1210/jcem.82.7.4042.
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Homozygosity for the multiple endocrine neoplasia type 1 (MEN1) gene mutation was described in two of three affected siblings of a kindred in which both parents and the third daughter were heterozygotes. Surprisingly, in the two homozygotes, the disease history did not differ from the one of the heterozygotes. In the attempt to unravel genetic differences in parathyroid tumorigenesis between homozygotes and heterozygotes, restriction fragment length polymorphism analysis and microsatellite PCR analysis for loss of heterozygosity (LOH) at the MEN1 gene region on chromosome 11q13 was performed in parathyroid tissues removed at surgery from the mother, her heterozygous sister, and the three siblings. Allelic losses were evidenced in the larger glands of each patient, with a similar pattern of chromosome 11q12–13 losses. The somatic mutation consisted of a large loss of genetic material from chromosome 11. No gross differences exist in the 11q12–13 LOH observed between homozygous and heterozygous carriers. Interestingly, one of the parathyroid tumors from one heterozygote exhibited region of skipped LOH at the 11q12–13 region. The region in the depth of the critical interval retained heterozygosity, whereas those flanking it shared LOH. These findings indicate that inactivation of both copies of the MEN1 gene are not sufficient for parathyroid tumor development in MEN 1 patients and that tumor suppressor genes, other than the MEN1 gene on chromosome 11 or on other chromosomes, can be involved in the pathogenesis of parathyroid tumorigenesis in MEN 1 syndrome.
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Dai, K., C. B. Gillies e A. E. Dollin. "Synaptonemal complex analysis of domestic sheep (Ovis aries) with Robertsonian translocations. II. Trivalent and pairing abnormalities in Massey I and Massey II heterozygotes". Genome 37, n.º 4 (1 de agosto de 1994): 679–89. http://dx.doi.org/10.1139/g94-096.
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Zygotene and pachytene spermatocytes from Massey I (t1 5;26) and Massey II (t2 8;11) translocation heterozygotes each contained one trivalent, often delayed in pairing, while cells from double Massey translocation heterozygotes had two such trivalents. As meiosis progressed, trivalents became fully paired, with acrocentric axes in a cis configuration. Abnormal pairing configurations often resulted from interactions between unpaired chromosome axes or segments. However, when two Massey trivalents were present in the same nucleus, there was no pairing interaction between them. In different Massey translocation heterozygotes, trivalent-involved pairing abnormalities occurred in 14–28% of cells, with XY–trivalent and XY–bivalent–trivalent associations being as high as 7.1–23.1%. In spermatocytes from single and double Massey translocation heterozygotes with normal-sized testes, the total SC abnormality frequency was 34.4% for the t1 heterozygotes, 27.1% for the t2 heterozygotes, and 21.4% for the double heterozygote. One Massey II heterozygote with one normal and one small testis had significantly higher SC abnormality frequency (54%) than normal rams. A trisomic cell was recorded in one ram and two hyperdiploid cells in another ram, but these were unrelated to the translocations. It is suggested that resolution of pairing abnormalities by synaptic adjustment is important in reducing the effects on fertility of the translocations.Key words: sheep, Robertsonian translocation, trivalent, abnormal pairing configuration.
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Ng, Kevin, Erron W. Titus, Krystien V. Lieve, Thomas M. Roston, Andrea Mazzanti, Frederick H. Deiter, Isabelle Denjoy et al. "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2 -Catecholaminergic Polymorphic Ventricular Tachycardia". Circulation 142, n.º 10 (8 de setembro de 2020): 932–47. http://dx.doi.org/10.1161/circulationaha.120.045723.
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Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0; P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1; P <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. Conclusions: This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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Bonvicino, Cibele R., Paulo S. D'Andrea e Pavel M. Borodin. "Pericentric inversion in natural populations of Oligoryzomys nigripes (Rodentia: Sigmodontinae)". Genome 44, n.º 5 (1 de outubro de 2001): 791–96. http://dx.doi.org/10.1139/g01-080.
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We analysed polymorphism for pericentric inversion in chromosome 3 of Oligoryzomys nigripes (Rodentia: Sigmodontinae) in several populations in Brazil and examined the meiotic behaviour of this chromosome in heterozygotes. We observed an orderly pairing of all chromosomes at pachytene in heterozygotes for the inverted chromosome 3. No indication of meiotic arrest and germ-cell death was found. Electron microscopy of synaptonemal complexes and conventional meiotic analysis indicated strictly nonhomologous synapsis and crossing-over suppression in the inverted region in the heterozygotes, which prevent the formation of unbalanced gametes. Thus, the pericentric inversion in chromosome 3 does not apparently result in any selective disadvantages in heterozygous carriers. In the majority of the populations studied, the frequencies of acrocentric homozygotes, metacentric homozygotes, and heterozygotes were in HardyWeinberg equilibrium. However, in some populations, we detected an excess of heterozygotes and a deficiency of acrocentric homozygotes.Key words: chromosome rearrangements, inversion, meiosis, Oligoryzomys nigripes.
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Rossi, Enrico, Max K. Bulsara, John K. Olynyk, Digby J. Cullen, Lesa Summerville e Lawrie W. Powell. "Effect of Hemochromatosis Genotype and Lifestyle Factors on Iron and Red Cell Indices in a Community Population". Clinical Chemistry 47, n.º 2 (1 de fevereiro de 2001): 202–8. http://dx.doi.org/10.1093/clinchem/47.2.202.
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Abstract Background: Heterozygotes for the C282Y mutation of the HFE gene may have altered hematology indices and higher iron stores than wild-type subjects. Methods: We performed a cross-sectional analysis of 1488 females and 1522 males 20–79 years of age drawn from the Busselton (Australia) population study to assess the effects of HFE genotype, age, gender, and lifestyle on serum iron and hematology indices. Results: Male C282Y heterozygotes had increased transferrin saturation compared with the wild-type genotype. Neither male nor female heterozygotes had significantly increased ferritin values compared with the wild-type genotype. Younger (20–29 years) wild-type males, but not heterozygous males, had significantly lower ferritin values than wild-type males in the older age groups. Compound heterozygous subjects had increased means for serum iron, transferrin saturation, corpuscular volume, and corpuscular hemoglobin compared with the wild-type genotype, and the males also had increased ferritin values (medians 323 vs 177 μg/L; P = 0.003). In both male and female wild-type subjects, an increased body mass index was associated with decreased serum iron and transferrin saturation and increased ferritin values. There was a significant increase in ferritin concentrations in both genders with increasing frequency of red meat consumption above a baseline of 1–2 times per week and alcohol intakes >10 g/day. Conclusions: Male C282Y heterozygotes had significantly increased transferrin saturation values. Compound heterozygous (C282Y/H63D) subjects formed a separate category of C282Y heterozygotes in whom both iron and red cell indices were significantly increased compared with the wild-type genotype.
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Girolami, Antonio, Elisabetta Cosi, Silvia Ferrari, Bruno Girolami e Maria L. Randi. "Thrombotic Events in Homozygotes with a Proven or Highly Probable Arg304Gln Factor VII Mutation (FVII Padua)1): Only Limited Replacement Therapy is Needed in Case of Surgery". Cardiovascular & Hematological Disorders-Drug Targets 19, n.º 3 (21 de outubro de 2019): 233–38. http://dx.doi.org/10.2174/1871529x19666190308114842.
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Objective: To investigate the prevalence of thrombotic events among patients with proven or highly probable homozygosis for the Arg304Gln (Factor VII Padua) defect or compound heterozygosis containing the Arg304Gln mutation. Methods: Homozygotes and compound heterozygotes proven by molecular studies to have the Arg304Gln mutation were gathered from personal files and from two PubMed searches. In addition, patients with probable homozygosis on the basis of clotting tests (discrepancies among Factor VII activity levels according to the tissue thromboplastin used) were also gathered. Results: 30 proven homozygotes and 17 probable ones were gathered together with 8 compound heterozygotes. In the latter use, the associated mutation was Cys135Arg (twice), Gly180Arg, Arg304Trp, Arg315Trp, His348Gln, Gly365Cys. The prevalence of venous thrombotic events was 16.6, 11.8 and 11.1 percent, respectively for the three groups of patients. Heterozygotes showed no thrombotic event. The difference for proven homozygotes was statistically significant, while for the other groups only a trend was present. Conclusion: proven homozygous or compound heterozygous patients with the Arg304Gln mutation showed a higher than expected incidence of thrombotic events. The same is true for probable cases gathered only on the basis of clotting tests. These patients, because of their frequent lack of bleeding and for their relatively high prevalence of thrombosis should probably receive only limited replacement therapy in case of surgical procedures.
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McClelland, Erin E., Dustin J. Penn e Wayne K. Potts. "Major Histocompatibility Complex Heterozygote Superiority during Coinfection". Infection and Immunity 71, n.º 4 (abril de 2003): 2079–86. http://dx.doi.org/10.1128/iai.71.4.2079-2086.2003.
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ABSTRACT Genes of the major histocompatibility complex (MHC) play a critical role in immune recognition, and many alleles confer susceptibility to infectious and autoimmune diseases. How these deleterious alleles persist in populations is controversial. One hypothesis postulates that MHC heterozygote superiority emerges over multiple infections because MHC-mediated resistance is generally dominant and many allele-specific susceptibilities to pathogens will be masked by the resistant allele in heterozygotes. We tested this hypothesis by using experimental coinfections with Salmonella enterica (serovar Typhimurium C5TS) and Theiler's murine encephalomyelitis virus (TMEV) in MHC-congenic mouse strains where one haplotype was resistant to Salmonella and the other was resistant to TMEV. MHC heterozygotes were superior to both homozygotes in 7 out of 8 comparisons (P = 0.0024), and the mean standardized pathogen load of heterozygotes was reduced by 41% over that of homozygotes (P = 0.01). In contrast, no heterozygote superiority was observed when the MHC haplotype combinations had similar susceptibility profiles to the two pathogens. This is the first experimental evidence for MHC heterozygote superiority against multiple pathogens, a mechanism that would contribute to the evolution of MHC diversity and explain the persistence of alleles conferring susceptibility to disease.
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Aghamohammadi, Asghar, Seyed M. Akrami, Marjan Yaghmaie, Nima Rezaei, Gholamreza Azizi, Mehdi Yaseri, Hassan Nosrati e Majid Zaki-Dizaji. "Individual Radiosensitivity Assessment of the Families of Ataxia-Telangiectasia Patients by G2-Checkpoint Abrogation". Sultan Qaboos University Medical Journal [SQUMJ] 18, n.º 4 (28 de março de 2019): 440. http://dx.doi.org/10.18295/squmj.2018.18.04.003.
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Objectives: Ataxia-telangiectasia (A-T) is an autosomal recessive multisystem disorder characterised by cerebellar degeneration, telangiectasia, radiation sensitivity, immunodeficiency, oxidative stress and cancer susceptibility. Epidemiological research has shown that carriers of the heterozygous ataxia-telangiectasia mutated (ATM) gene mutation are radiosensitive to ionising irradiation and have a higher risk of cancers, type 2 diabetes and atherosclerosis. However, there is currently no fast and reliable laboratory-based method to detect heterozygous ATM carriers for family screening and planning purposes. This study therefore aimed to evaluate the ability of a modified G2-assay to identify heterozygous ATM carriers in the families of A-T patients. Methods: This study took place at the Tehran University of Medical Sciences, Tehran, Iran, between February and December 2017 and included 16 A-T patients, their parents (obligate heterozygotes) and 30 healthy controls. All of the subjects underwent individual radiosensitivity (IRS) assessment using a modified caffeine-treated G2-assay with G2-checkpoint abrogation. Results: The mean IRS of the obligate ATM heterozygotes was significantly higher than the healthy controls (55.13% ± 5.84% versus 39.03% ± 6.95%; P <0.001), but significantly lower than the A-T patients (55.13% ± 5.84% versus 87.39% ± 8.29%; P = 0.001). A receiver operating characteristic (ROC) curve analysis of the G2-assay values indicated high sensitivity and specificity, with an area under the ROC curve of 0.97 (95% confidence interval: 0.95–1.00). Conclusion: The modified G2-assay demonstrated adequate precision and relatively high sensitivity and specificity in detecting heterozygous ATM carriers.Keywords: Ataxia-Telangiectasia; Chromosome Breakage; Genetic Carrier Screening; Heterozygote; Radiation Sensitivity; Sensitivity and Specificity.
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Yap, S., K. A. O’Donnell, C. O’Neill, P. D. Mayne, P. Thornton e E. Naughten. "Factor V Leiden (Arg506Gln), a Confounding Genetic Risk Factor but not Mandatory for the Occurrence of Venous Thromboembolism in Homozygotes and Obligate Heterozygotes for Cystathionine β-synthase Deficiency". Thrombosis and Haemostasis 81, n.º 04 (1999): 502–5. http://dx.doi.org/10.1055/s-0037-1614513.
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SummaryThrombosis is the major cause of morbidity and mortality in individuals with untreated classical homocystinuria (HCU) due to cystathionine β-synthase deficiency and characterised by severe hyperhomocysteinaemia. In addition, mild and moderate hyperhomocysteinaemia and Factor V Leiden (FVL; Arg506Gln) have recently been identified as thrombotic risk factors. FVL, which renders resistance to activated Protein C, is the most common inherited genetic risk factor for thrombosis with a high allelic frequency amongst Caucasians. As thrombophilia is a multigenic disorder, 26 individuals with HCU (median age 17.6 years, range 3.5-32.8 years) and 36 obligate heterozygotes (median age 51.5 years, range 34-74 years) were screened for FVL. All the HCU individuals received treatment, except one, within 6 weeks of birth for those who were diagnosed at birth through the national newborn screening programme (n = 20) and at the time of diagnosis for those late detected (n = 5, mean age of starting treatment 4.9 years, range 1.4-11 years). All had been free from venous thrombosis, except one HCU individual and one HCU obligate heterozygote. Neither of the two individuals with venous thrombosis carried FVL. Two independent individuals with HCU (male 14.8 years; female 18.2 years) were heterozygous for FVL (allelic frequency 3.8%) and three independent HCU obligate heterozygotes (males 40 and 45.8 years; female 45.6 years) were also heterozygous for FVL (allelic frequency 4.16%). The findings in this small group suggest that FVL is not a mandatory but a significant confounding risk factor for the occurrence of thrombosis in HCU individuals and additional contributing factors may be required for thrombosis to occur in HCU obligate heterozygotes with FVL heterozygosity. Our data also suggest that treatment of HCU not only reduces the thrombotic risk in patients with isolated HCU but also in those with the additional FVL heterozygosity.
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Ji, Yuanfu, Wayne A. Raska, Marcos De Donato, M. Nurul Islam-Faridi, H. James Price e David M. Stelly. "Identification and distinction among segmental duplication-deficiencies by fluorescence in situ hybridization (FISH)-adorned multivalent analysis". Genome 42, n.º 4 (1 de agosto de 1999): 763–71. http://dx.doi.org/10.1139/g99-012.
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Most simple reciprocal translocation homozygotes and heterozygotes are euploid, and normal in genotype. However, translocation heterozygotes form six types of numerically balanced meiotic products. The cross of a translocation heterozygote with a normal individual can yield normal progeny, translocation heterozygotes, or any of four segmentally aneuploid duplication-deficient types (dp-dfs). Using metaphase I configuration analysis, most dp-dfs can be distinguished easily from normal and heterozygous translocations. However, identification of the four dp-df types is often impossible unless there is an appreciable karyotypic difference in arm size, relative breakpoint position, or a diagnostic cytological marker. Here we demonstrated the utility and facility of dp-df identification by means of meiotic fluorescence in situ hybridization (FISH) to adorn one chromosome arm with a molecular marker. The rationale is presented diagrammatically, and exemplified by identifying both adjacent-1 and adjacent-2 dp-dfs in Gossypium hirsutum. Polymorphism is not required among marker loci, so analysis of dp-dfs can proceed without requirement of sexual hybridization or sophisticated high-polymorphism marker systems. Besides facilitating the identification of dp-dfs, such an analysis can provide facile means to assign marker loci to chromosomes, arms, and segments. Integrative mapping of chromosomal, physical, and recombination maps will thus be facilitated. An ability to readily distinguish adjacent-1 and adjacent-2 types of dp-dfs should also enhance strategic derivation of other aneuploids, e.g., dp-df related monosomes and trisomes.Key words: Gossypium, cotton, duplication-deficiency, fluorescence in situ hybridization, repetitive DNA.
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Ro, Seungil, Sung Jin Hwang, Melodie Muto, William Keith Jewett e Nick J. Spencer. "Anatomic modifications in the enteric nervous system of piebald mice and physiological consequences to colonic motor activity". American Journal of Physiology-Gastrointestinal and Liver Physiology 290, n.º 4 (abril de 2006): G710—G718. http://dx.doi.org/10.1152/ajpgi.00420.2005.
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It has been assumed that in piebald lethal mice that develop megacolon, impaired colonic motor activity is restricted to the aganglionic distal colon. Peristaltic mechanical recordings, immunohistochemistry, and quantitative PCR were used to investigate whether regions of the colon, other than the aganglionic segment, may also show anatomical modifications and dysfunctional colonic motor activity. Contrary to expectations, colonic migrating motor complexes (MMCs) were absent along the whole colon of piebald lethal homozygote mice and severely impaired in heterozygote siblings. Aganglionosis was detected not only in the distal colon of piebald homozygote lethal mice (mean length: 20.4 ± 2.1 mm) but also surprisingly in their heterozygote siblings (mean length: 12.4 ± 1.1 mm). Unlike homozygote lethal mice, piebald heterozygotes showed no signs of megacolon. Interestingly, mRNA expression for PGP 9.5 was also dramatically reduced (by 71–99%) throughout the entire small and large bowel in both homozygote lethal and heterozygous littermates (by 67–87%). Histochemical staining confirmed a significant reduction in myenteric ganglia along the whole colon. In summary, the piebald mutation in homozygote lethal and heterozygote siblings is associated with dramatic reductions in myenteric ganglia throughout the entire colon and not limited to the distal colon as originally thought. Functionally, this results in an absence or severe impairment of colonic MMC activity in both piebald homozygote lethal and heterozygote siblings, respectively. The observation that piebald heterozygotes have an aganglionic distal colon (mean length: 12 mm) but live a normal murine life span without megacolon suggests that aganglionosis >12 mm and the complete absence of colonic MMCs may be required before any symptoms of megacolon arise.
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Plöchl, E., J. P. Colombo, B. Wermuth e K. M. Gibson. "Increased plasma amylase in the family of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency". Clinical Chemistry 38, n.º 2 (1 de fevereiro de 1992): 307–9. http://dx.doi.org/10.1093/clinchem/38.2.307.
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Abstract A patient with 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase, EC 4.1.3.4) deficiency presented consistently above-normal values of plasma amylase (EC 3.2.1.1). Activities measured were in the lower normal range in family members not proven heterozygotes and in the upper normal range in the proven heterozygotes. Heterozygosity was proven by intermediate HMG-CoA lyase activities determined in cultured fibroblasts and in lymphocytes in the parents and the paternal grandmother. Because all of the family members had diseases of the pancreas, colon, and liver, we question whether the heterozygote state contributes to the impaired function of these organs. Our findings of significantly increased amylase activities in the heterozygotes and the patient, in comparison with the other family members, support this hypothesis.
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Ho, PJ, J. Rochette, CA Fisher, B. Wonke, MK Jarvis, A. Yardumian e SL Thein. "Moderate reduction of beta-globin gene transcript by a novel mutation in the 5' untranslated region: a study of its interaction with other genotypes in two families". Blood 87, n.º 3 (1 de fevereiro de 1996): 1170–78. http://dx.doi.org/10.1182/blood.v87.3.1170.bloodjournal8731170.
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We have identified two individuals of Greek Cypriot origin with thalassemia intermedia. Molecular analysis has shown that each individual is a compound heterozygote for a previously described beta zero thalassemia allele and a novel mutation, C-->G in position +33, in the 5′ untranslated region of the beta globin gene. In both families the beta +33 allele is associated with the same beta haplotype (-++- ) suggesting that it is likely to be of a single origin, beta-cDNAs from normal and mutant beta alleles were isolated from peripheral blood reticulocytes using the technique of reverse transcription-polymerase chain reaction. Because the beta +33 (C-->G) mutation creates a cutting site for the restriction enzyme NlalV, we could demonstrate by differential restriction analysis that the beta gene with +33 mutation showed 25% to 35% residual activity compared with normal. The additive effect of this moderate deficit in beta globin production with the beta zero thalassemia mutation would explain the clinical phenotypes observed in the two probands. In contrast, two siblings of one proband who were also compound heterozygotes for the same beta thalassemia mutations, as well as heterozygotes for a nondeletional alpha thalassemia variant, and two other compound heterozygotes for the beta +33 and a beta+ thalassemia allele were completely asymptomatic. Individuals heterozygous for the beta +33 C-G mutation alone are clinically and hematologically silent, with normal red blood cell indices and normal levels of hemoglobin (Hb) A2. A direct relationship between genotypic and phenotypic severity is clearly demonstrated in these cases with obvious implications for prenatal diagnosis.
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Leebeek, F. W. G., J. Stibbe, E. A. R. Knot, C. Kluft, M. J. Gomes e M. Beudeker. "Mild Haemostatic Problems Associated with Congenital Heterozygous α2-Antiplasmin Deficiency". Thrombosis and Haemostasis 59, n.º 01 (1988): 096–100. http://dx.doi.org/10.1055/s-0038-1646773.
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SummaryA Dutch family, of which 13 members are heterozygotes, deficient for α2-antiplasmin (α2-AP) is reported. Clinical studies showed that 2 heterozygotes had a mild bleeding tendency, which presented as bleeding episodes after tooth extraction and after surgery and, in one patient, also as excessive menstruation. Laboratory investigations revealed an α2-AP activity of 62% (51-71) (median and range) and an antigen level of 60% (60-66). The plasminogen binding as well as the fibrin binding properties of α2-AP were normal. Plasminogen concentrations were significantly higher in the heterozygotes compared to the other family members. However, free plasminogen not bound to histidine-rich glycoprotein was not significantly different between these two groups. We propose that in this family the deficiency of α2-AP is due to a decreased synthesis of a normal α2-AP molecule. This present study brings the frequency of heterozygous α2-AP deficient patients with a bleeding tendency to 13 out of 59 heterozygotes reported in the literature.
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Suh, Ji Hyung, Ik Hee Ryu, Jin Pyo Hong, Ja Yoon Moon, Jin Seok Choi, Ikhyun Jun, Tae-Im Kim e Eung Kweon Kim. "Phenotypes of Granular Corneal Dystrophy Type 2 among Koreans in Their Twenties". Journal of the Korean Ophthalmological Society 63, n.º 12 (15 de dezembro de 2022): 965–72. http://dx.doi.org/10.3341/jkos.2022.63.12.965.
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Purpose: Granular corneal dystrophy type 2 (GCD2) is a hereditary disease that features granular and lattice stromal deposits in the cornea. There are homozygotes and heterozygotes and the opacities are exacerbated by corneal trauma or surgery, such as laser in situ keratomileusis (LASIK). As there is individual variability in GCD2 phenotypes, we investigated various corneal features of GCD2 patients in their twenties, the main age group for refractive surgery.Methods: From genetically confirmed GCD2 patients who had an R124H mutation of the transforming growth factor β induced (<i>TGFBI</i>) gene at age 20 to 29 years, we chose representative patients: one homozygote; one compound heterozygote; one simple heterozygote with a severe phenotype with many granular deposits; one common heterozygote; and four heterozygotes with normal corneas. The corneas of all patients were subject to slit-lamp examination and photographed.Results: The homozygote had confluent granular deposits covering the cornea. The compound heterozygote had granular and lattice deposits covering the center of the cornea. The patient with a severe phenotype had more than 30 granular deposits in one eye, but was a simple GCD2 heterozygote, verified by full-sequencing of the <i>TGFBI</i> gene. In the four patients with normal corneas, a single small lesion was subsequently detected during follow-up in two, at 3 weeks and 6 months, respectively. Both corneas were judged clear at chance examinations.Conclusions: Among Koreans in their twenties, GCD2 patients have various phenotypes, from clear corneas to severe confluent opacities. There are GCD2 heterozygotes with nearly clear corneas, so caution must be taken when choosing patients for refractive surgery.
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Szatkowska, Iwona, Wilhelm Grzesiak, Magdalena Jędrzejczak, Andrzej Dybus, Daniel Zaborski e Dorota Jankowiak. "An analysis of CYP19, CYP21 and ER genotypes in Polish Holstein-Friesian cows with regard to the selected reproductive traits". Acta Veterinaria Brno 80, n.º 1 (2011): 65–71. http://dx.doi.org/10.2754/avb201180010065.
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The aim of this study was to relate polymorphic variants of CYP19, CYP21 and ER1 genes to reproductive traits in 472 Polish Holstein-Friesian cows. High frequencies of one of the homozygous genotypes were found. The ER1/SnaBIAA homozygotes were not identified. In the first and third lactation, an average calving-to-conception interval (CLVC) in cows of ER1/SnaBIGG genotype was significantly shorter (P ≤ 0.05) than in heterozygous cows. In the cows of ER1/BglIGG genotype, significantly shorter CLVC (P ≤ 0.05) was observed compared to heterozygotes in the first lactation, whereas in the third lactation, CLVC in homozygous cows was significantly longer (P ≤ 0.05) than in heterozygous ones. It was also found that homozygous cows were characterized by significantly longer calving interval (CLVI; P ≤ 0.05) compared to heterozygotes in the third lactation. Longer CLVCs in CYP19AA cows were found, compared to heterozygotes, and this difference was significant in the first and third lactation (P ≤ 0.05). Similarly, the average CLVIs were longer in CYP19AA homozygotes than in heterozygous cows; however, significance was proven only in the third lactation (P ≤ 0.05). Description of the molecular mechanisms regulating reproduction, and thus identification of the individuals of genotypes with optimal potential may facilitate the employment of selected reproductive model by a breeder.
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Jones, G., S. Zammit, N. Norton, M. L. Hamshere, S. J. Jones, C. Milham, R. D. Sanders et al. "Aggressive behaviour in patients with schizophrenia is associated with catechol-O-methyltransferase genotype". British Journal of Psychiatry 179, n.º 4 (outubro de 2001): 351–55. http://dx.doi.org/10.1192/bjp.179.4.351.
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BackgroundEvidence exists for an association between aggression and schizophrenia. Although the aetiology of aggression is multifactorial, three studies have reported associations between polymorphisms of the catechol-O-methyltransferase (COMT) gene and aggression in schizophrenia.AimsTo replicate these findings in a larger sample using the Overt Aggression Scale (OAS).MethodA sample of 180 people with DSM–IV schizophrenia were rated for aggression using the OAS. Kruskal–Wallis and contingency table analyses were applied to the OAS results.ResultsThe high-activity homozygotes showed significantly higher scores of aggression, whereas the heterozygotes showed significantly lower scores. The odds ratio for aggression for the high-activity homozygotes was 2.07 (95% Cl=1.03–4.15), whereas that for the heterozygotes was 0.54 (95% CI=0. 30–1.00).ConclusionsThe high-activity COMT homozygote confers a higher risk of recorded aggression in schizophrenia. Heterozygotes had a significantly lower risk, which may represent an example of heterosis/heterozygote advantage.
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Herrmann, Mark G., Jacob D. Durtschi, Carl T. Wittwer e Karl V. Voelkerding. "Expanded Instrument Comparison of Amplicon DNA Melting Analysis for Mutation Scanning and Genotyping". Clinical Chemistry 53, n.º 8 (1 de agosto de 2007): 1544–48. http://dx.doi.org/10.1373/clinchem.2007.088120.
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Abstract Background: Additional instruments have become available since instruments for DNA melting analysis of PCR products for genotyping and mutation scanning were compared. We assessed the performance of these new instruments for genotyping and scanning for mutations. Methods: A 110-bp fragment of the β-globin gene including the sickle cell anemia locus (HBB c. 20A>T) was amplified by PCR in the presence of LCGreen Plus or SYBR Green I. Amplicons of 4 different genotypes [wild-type, homozygous, and heterozygous HBB c. 20A>T and double-heterozygote HBB c. (9C>T; 20A>T)] were melted on 7 different instruments [Applied Biosystems 7300, Corbett Life Sciences Rotor-Gene 6500HRM, Eppendorf Mastercycler RealPlex4S, Idaho Technology LightScanner (384 well), Roche LightCycler 480 (96 and 384 well) and Stratagene Mx3005p] at a rate of 0.61 °C/s or when this was not possible, at 0.50 °C steps. We evaluated the ability of each instrument to genotype by melting temperature (Tm) and to scan for heterozygotes by curve shape. Results: The ability of most instruments to accurately genotype single-base changes by amplicon melting was limited by spatial temperature variation across the plate (SD of Tm = 0.020 to 0.264 °C). Other variables such as data density, signal-to-noise ratio, and melting rate also affected heterozygote scanning. Conclusions: Different instruments vary widely in their ability to genotype homozygous variants and scan for heterozygotes by whole amplicon melting analysis. Instruments specifically designed for high-resolution melting, however, displayed the least variation, suggesting better genotyping accuracy and scanning sensitivity and specificity.
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Rosendaal, Frits, Marco Cattaneo, Maurizio Margaglione, Valerio De Stefano, Tony Cumming, Valder Arruda, Andreas Hillarp, Jean-Luc Reny e Joseph Emmerich. "Combined Effect of Factor V Leiden and Prothrombin 20210A on the Risk of Venous Thromboembolism". Thrombosis and Haemostasis 86, n.º 09 (2001): 809–16. http://dx.doi.org/10.1055/s-0037-1616136.
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SummaryFactor V Leiden and factor II G20210A mutations are two frequent genetic risk factors involved in venous thromboembolism (VTE). The goal of this pooled analysis of 8 case-control studies, comprising a total of 2310 cases and 3204 controls, was to precisely estimate the risk of VTE in patients bearing both mutations (double heterozygotes). Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation. Fifty-one cases (2.2%) and none of the controls were double heterozygotes. The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1). Twelve percent of patients heterozygous for factor V Leiden were also heterozygous for factor II G20210A and conversely 23% of patients heterozygous for factor II G20210A were also heterozygous for factor V Leiden. Furthermore, in this large population we analyzed the effect of oral contraceptive (OC) in women carrying one of these mutations. Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-18.45). The odds ratio of the association of factor II mutation and OC use was 7.14 (3.39-15.04). Finally, we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups.
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Shanmugam, V., K. W. Sell e B. K. Saha. "Mistyping ACE heterozygotes." Genome Research 3, n.º 2 (1 de outubro de 1993): 120–21. http://dx.doi.org/10.1101/gr.3.2.120.
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Powell, Lawrie W., e Elizabeth C. Jazwinska. "Hemochromatosis in Heterozygotes". New England Journal of Medicine 335, n.º 24 (12 de dezembro de 1996): 1837–39. http://dx.doi.org/10.1056/nejm199612123352410.
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Swift, Michael. "Manifestations in heterozygotes". American Journal of Medical Genetics 39, n.º 4 (15 de junho de 1991): 501. http://dx.doi.org/10.1002/ajmg.1320390431.
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Katoh, Masaya, e David W. Foltz. "Biochemical evidence for the existence of a null allele at the leucine aminopeptidase-2 (Lap-2) locus in the oyster Crassostrea virginica (Gmelin)". Genome 32, n.º 4 (1 de agosto de 1989): 687–90. http://dx.doi.org/10.1139/g89-499.
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The existence of a null activity allele at the leucine aminopeptidase-2 (Lap-2) locus in the oyster Crassostrea virginica (Gmelin) was previously inferred from anomalous segregation patterns observed in offspring from pair crosses, and from the occurrence of individuals lacking Lap-2 bands on gels (presumed null homozygotes). The present research was done to determine whether leucine aminopeptidase specific activity was significantly reduced in oysters presumed from breeding experiments to be heterozygous for a Lap-2 null allele. Approximately thirty 4-month-old oysters from each of two crosses were analyzed. In each cross, LAP specific activity was significantly reduced (P < 0.001) in active/null heterozygotes, compared with full-sib oysters that were active/active heterozygotes. On average, active/null heterozygotes had 57% of the activity of the corresponding active/active heterozygotes.Key words: oysters, null allele, leucine aminopeptidase.
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Zhang, Jianning, Daniel G. Fuster, Mary Ann Cameron, Henry Quiñones, Carolyn Griffith, Xiao-Song Xie e Orson W. Moe. "Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit". American Journal of Physiology-Renal Physiology 307, n.º 9 (1 de novembro de 2014): F1063—F1071. http://dx.doi.org/10.1152/ajprenal.00408.2014.
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Congenital distal renal tubular acidosis (RTA) from mutations of the B1 subunit of V-ATPase is considered an autosomal recessive disease. We analyzed a distal RTA kindred with a truncation mutation of B1 (p.Phe468fsX487) previously shown to have failure of assembly into the V1domain of V-ATPase. All heterozygous carriers in this kindred have normal plasma HCO3−concentrations and thus evaded the diagnosis of RTA. However, inappropriately high urine pH, hypocitraturia, and hypercalciuria were present either individually or in combination in the heterozygotes at baseline. Two of the heterozygotes studied also had inappropriate urinary acidification with acute ammonium chloride loading and an impaired urine-blood Pco2gradient during bicarbonaturia, indicating the presence of a H+gradient and flux defects. In normal human renal papillae, wild-type B1 is located primarily on the plasma membrane, but papilla from one of the heterozygote who had kidney stones but not nephrocalcinosis showed B1 in both the plasma membrane as well as diffuse intracellular staining. Titration of increasing amounts of the mutant B1 subunit did not exhibit negative dominance over the expression, cellular distribution, or H+pump activity of wild-type B1 in mammalian human embryonic kidney-293 cells and in V-ATPase-deficient Saccharomyces cerevisiae. This is the first demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of a mutant B1 subunit that cannot be attributable to negative dominance. We propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency. B1 heterozygosity should be considered in patients with calcium nephrolithiasis and urinary abnormalities such as alkalinuria or hypocitraturia.
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Gundry, Cameron N., Joshua G. Vandersteen, Gudrun H. Reed, Robert J. Pryor, Jian Chen e Carl T. Wittwer. "Amplicon Melting Analysis with Labeled Primers: A Closed-Tube Method for Differentiating Homozygotes and Heterozygotes". Clinical Chemistry 49, n.º 3 (1 de março de 2003): 396–406. http://dx.doi.org/10.1373/49.3.396.
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Abstract Background: Common methods for identification of DNA sequence variants use gel electrophoresis or column separation after PCR. Methods: We developed a method for sequence variant analysis requiring only PCR and amplicon melting analysis. One of the PCR primers was fluorescently labeled. After PCR, the melting transition of the amplicon was monitored by high-resolution melting analysis. Different homozygotes were distinguished by amplicon melting temperature (Tm). Heterozygotes were identified by low-temperature melting of heteroduplexes, which broadened the overall melting transition. In both cases, melting analysis required ∼1 min and no sample processing was needed after PCR. Results: Polymorphisms in the HTR2A (T102C), β-globin [hemoglobin (Hb) S, C, and E], and cystic fibrosis (F508del, F508C, I507del, I506V) genes were analyzed. Heteroduplexes produced by amplification of heterozygous DNA were best detected by rapid cooling (>2 °C/s) of denatured products, followed by rapid heating during melting analysis (0.2–0.4 °C/s). Heterozygotes were distinguished from homozygotes by a broader melting transition, and each heterozygote had a uniquely shaped fluorescent melting curve. All homozygotes tested were distinguished from each other, including Hb AA and Hb SS, which differed in Tm by <0.2 °C. The amplicons varied in length from 44 to 304 bp. In place of one labeled and one unlabeled primer, a generic fluorescent oligonucleotide could be used if a 5′ tail of identical sequence was added to one of the two unlabeled primers. Conclusion: High-resolution melting analysis of PCR products amplified with labeled primers can identify both heterozygous and homozygous sequence variants.
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Bombardier, Chris, Linda J. Jacobson, Marilyn J. Manco-Johnson e Neil A. Goldenberg. "Evidence of Increased Plasma Coagulative Capacity by CloFAL Assay among Pediatric Factor V Leiden and Prothrombin G20210A Heterozygotes with, Versus without, a First-or Second-Degree Family History of Venous Thromboembolism". Blood 112, n.º 11 (16 de novembro de 2008): 5345. http://dx.doi.org/10.1182/blood.v112.11.5345.5345.
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Abstract BACKGROUND: The factor V (FV) Leiden and prothrombin (PT) G20210A polymorphisms in heterozygous state are present in 5% and 1–2% of Caucasians, respectively, and confer approximately 5-fold and 2-fold increases in the risk of incident venous thromboembolism (VTE). While some families who carry these genetic thrombophilia traits exhibit a prothrombotic phenotype, others have no (or only a limited) history of VTE. The ability to discern which individuals with personal and familial carriage of these genetic thrombophilias possess a clinically meaningful increase in VTE risk remains elusive, and (particularly among children) is perhaps best informed presently by family history of VTE. OBJECTIVE AND HYPOTHESES: We sought to evaluate overall plasma coagulative capacity in FV Leiden and PT G20210A heterozygotes using the Clot Formation and Lysis (CloFAL) assay, a global turbidimetric plasma assay of tissue-factor induced fibrin clot formation and tissue-type plasminogen activator enhanced fibrinolysis. We hypothesized that children heterozygous for either thrombophilia would not uniformly demonstrate hypercoagulability, but that coagulative capacity would be increased among heterozygotes who have a family history of VTE. PATIENTS AND METHODS: Children aged birth to 18 years (inclusive) enrolled in prospective inceptional cohort study of thrombosis/thrombophilia/stroke were included in the analysis if they were found to be heterozygous for FV Leiden or PT G20210A upon comprehensive thrombophilia testing and had undergone CloFAL assay testing on a research basis. Data on personal and family history of thrombotic events, thrombophilia testing, and CloFAL assay findings were analyzed. Intergroup comparisons of continuous data were performed by Mann-Whitney U test and proportions were compared between groups using chi-square or Fisher’s exact test, as appropriate. RESULTS: Characteristics of the study population are shown in Table 1. Approximately 70% of patients were evaluated for a family history of VTE (with/without known thrombophilia) and nearly 50% had personal histories of VTE or arterial ischemic stroke (AIS)/recurrent transient ischemic attack (TIA); those evaluated for events were significantly older than those without events, and this difference was statistically significant among those with a positive family history fo VTE. Hypercoagulability was shown in 50% of patients and hypofibrinolysis in 13% using the CloFAL assay. Plasma coagulative capacity and maximal amplitude (MA) of the CloFAL waveform were significantly increased in patients with, versus without, family history of VTE (coagulation index, CI: 102% vs. 72% of the adult normal pooled plasma standard, respectively, p=0.04; MA: 0.415 vs. 0.322, p=0.02), and were not explained by age differences between groups. However, in this relatively small study population, the proportion of CloFAL CI results that exceeded the upper limit of normal values did not significantly differ between those with, versus without, family history of VTE. Pediatric FV Leiden or PT G20210A heterozygotes with positive family history of VTE were more likely to have multi-trait (>1) thrombophilia, in which case a trend toward increased plasma coagulability was demonstrated (CI: 139% [multi-trait] vs. 86% [isolated trait]; p=0.07); superimposed thrombophilias in this group most often consisted of elevated factor VIII activity and Lp(a) concentration. CONCLUSIONS: The present findings using the CloFAL global assay indicate that, while pediatric FV Leiden or PT G20210A heterozygotes do not uniformly exhibit hypercoagulability, plasma coagulative capacity is nevertheless significantly increased among heterozgyotes who have a family history of VTE, which may relate to the presence of superimposed thrombophilias. Table 1. Summary characteristics of the study population. *VTE, AIS, or recurrent TIA **Two patients were dual heterozygotes. N 32 Median age at evaluation (range) 9.5 y (1–18 y) Personal history of events* 14 y (1–18 y) No personal history of events* 8 y (2–18 y) FV Leiden heterozygote (n) 26** PT G20210A heterozygote (n) 8** Personal history of VTE (n) 11 Personal history of AIS/recurrent TIA 4 Family history (1st/2nd degree) of VTE 71% Multi-trait (>1) thrombophilia 45% Acquired thrombophilia 24% Hypercoagulability by CloFAL assay 50% Hypofibrinolysis by CloFAL assay 13%
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Webb, A. J., P. Imlah e A. E. Carden. "Succinylcholine and halothane as a field test for the heterozygote at the halothane locus in pigs". Animal Science 42, n.º 2 (abril de 1986): 275–79. http://dx.doi.org/10.1017/s0003356100017992.
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ABSTRACTReaction to the muscle relaxant succinylcholine was investigated as a possible method of distinguishing the heterozygote from the normal homozygote at the halothane locus. Totals of 54 assumed heterozygotes and 67 assumed homozygotes received intravenous succinylcholine during halothane anaesthesia at 6 to 10 weeks of age. Three separate measures of the duration and severity of the muscular reaction to succinylcholine were all significantly increased in heterozygotes compared with homozygotes. The genotypic difference for one of the three reaction traits was significantly influenced by the day of testing. Due to overlapping distributions for the two genotypes, succinylcholine reactions did not offer a precise method of identifying individual heterozygotes. Although test mating to recessive homozygotes would still be required to be certain of eliminating the halothane gene, the gene frequency among prosepective parents for test mating could be substantially reduced by succinylcholine screening. Due to the expertise and time required, succinylcholine testing would probably only be worthwhile for the production of specialized homozygous lines at nucleus level.
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Simioni, Paolo, Elisabetta Castoldi, Barbara Lunghi, Daniela Tormene, Jan Rosing e Francesco Bernardi. "An underestimated combination of opposites resulting in enhanced thrombotic tendency". Blood 106, n.º 7 (1 de outubro de 2005): 2363–65. http://dx.doi.org/10.1182/blood-2005-04-1461.
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Abstract Heterozygous carriers of factor V (FV) Leiden who also carry FV deficiency often develop venous thromboembolism, but the thrombosis risk associated with this rare condition (pseudohomozygous activated protein C resistance) is still unclear. The thrombosis risk of genetically characterized pseudohomozygotes (n = 6) was compared with that of FV Leiden heterozygotes (n = 683) and homozygotes (n = 50) recruited within a large cohort study on familial thrombophilia. Both thrombin generation and Kaplan-Meier thrombosis-free survival analyses were performed in different FV genotype groups. FV Leiden pseudohomozygotes showed significantly higher thrombosis risk than heterozygotes. The thrombin generation test in pseudohomozygotes showed a pattern similar to homozygotes. Accordingly, early thrombotic manifestations occurred in pseudohomozygotes at a similar rate as in homozygotes. Thus, failure to recognize FV deficiency in FV Leiden heterozygotes may result in an underestimate of the thrombosis risk and inadequate management of affected patients.
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Prence, Elizabeth M., Cheryl A. Jerome, Barbara L. Triggs-Raine e Marvin R. Natwicz. "Heterozygosity for Tay-Sachs and Sandhoff Diseases among Massachusetts Residents with French Canadian Background". Journal of Medical Screening 4, n.º 3 (setembro de 1997): 133–36. http://dx.doi.org/10.1177/096914139700400304.
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Objectives— The frequency of Tay-Sachs disease (TSD) heterozygosity is increased among French Canadians in eastern Quebec. A large proportion of the New England population has French Canadian heritage; thus, it is important to determine if they too are at increased risk for TSD heterozygosity. This prospective study was designed to assess the TSD heterozygote frequency among people with French Canadian background living in Massachusetts. A simultaneous screen for heterozygosity for Sandhoff disease, a related genetic disorder, was also undertaken. Methods— 1260 non-pregnant subjects of French Canadian background were included in the study, β hexosaminidase activity was measured in blood samples, and results were evaluated for TSD and Sandhoff disease heterozygosity. Samples from the TSD heterozygotes were also subjected to mutation analysis. Results— Of the 1260 samples studied, 22 (1 in 57; CI 1 in 41, 1 in 98) were identified as TSD heterozygotes by enzymatic analyses and 11 subjects (1 in 114; CI 1 in 72,1 in 280) were identified as Sandhoff disease heterozygotes. Three of the 22 TSD heterozygotes were found to have benign pseudodeficiency mutations, resulting in a maximum TSD heterozygote frequency of 19 in 1260 (1 in 66; CI 1 in 46, 1 in 120). Together, these data provide a maximum frequency of heterozygosity for TSD or Sandhoff disease of 30 in 1260 (1 in 42; CI 1 in 31, 1 in 64) in this population. Conclusions— Simultaneous screening for TSD and Sandhoff disease heterozygosity by assay of β hexosaminidases A and B activities provides a possible method for use with subjects of French Canadian background. The relevance of some of the novel mutations identified in this group needs further study. However, the comparatively high combined frequency of TSD and Sandhoff disease heterozygosity indicates a need for discussion regarding the appropriateness of carrier testing for these disorders for persons of French Canadian background in Massachusetts.
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Phillips, R. B., M. P. Matsuoka, W. W. Smoker e A. J. Gharrett. "Inheritance of a chromosomal polymorphism in odd-year pink salmon from southeastern Alaska". Genome 42, n.º 5 (1 de outubro de 1999): 816–20. http://dx.doi.org/10.1139/g99-010.
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In previous work we found a high frequency of heterozygotes for a fission translocation involving the seventh chromosome pair in odd-year populations of pink salmon (Oncorhynchus gorbuscha) sampled from Washington State to south central Alaska. The populations from southeastern Alaska and northern British Columbia had high frequencies of heterozygotes for a second rearrangement of this same chromosome pair. In these fish one fission product, the larger acrocentric chromosome bearing the nucleolar organizer region (NOR), has undergone an inversion to produce a submetacentric chromosome. In this paper, we present inheritance data on pink salmon from the Gastineau hatchery stock in Juneau, Alaska, where individuals with the two rearrangements are found. Although most of the fish were either homozygous for the normal cytotype or heterozygous for the inversion cytotype, a few individuals heterozygous for the fission cytotype were found. Ten males and ten females were karyotyped, and crosses were set up in all combinations. Individuals with both rearrangements were found in crosses between the two types of heterozygotes, and the ratios of cytotypes in the progeny did not deviate significantly from the expected values. No significant difference in viability of offspring from crosses between individuals with different cytotypes was found up to the age of hatching.Key words: salmon, chromosomal polymorphism, translocation, inversion, cytotype.
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Chiang, Y. Jeffrey, Michael T. Hemann, Karen S. Hathcock, Lino Tessarollo, Lionel Feigenbaum, William C. Hahn e Richard J. Hodes. "Expression of Telomerase RNA Template, but Not Telomerase Reverse Transcriptase, Is Limiting for Telomere Length Maintenance In Vivo". Molecular and Cellular Biology 24, n.º 16 (15 de agosto de 2004): 7024–31. http://dx.doi.org/10.1128/mcb.24.16.7024-7031.2004.
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ABSTRACT Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT+/− heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR+/− heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed.
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Fairbrother, J. E., e A. R. Beaumont. "Heterozygote deficiencies in a cohort of newly settled Mytilus edulis spat". Journal of the Marine Biological Association of the United Kingdom 73, n.º 3 (agosto de 1993): 647–53. http://dx.doi.org/10.1017/s002531540003318x.
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A cohort of newly settled Mytilus edulis (L.) (Mollusca: Bivalvia) spat (mean shell length 530 µm) was collected from red filamentous algae at a site on the North Wales coast. After a period of growth in the laboratory, cellulose acetate and starch gel electrophoresis were used to investigate genotype frequencies at the Gpi, Odh, Lap, Pgm, Idh and Mpi loci. Individual testing of each locus, using the X2 test revealed significant deficiencies of heterozygotes at the Pgm, Mpi and Idh loci. However, further testing using a sequential Bonf erroni test, designed to assess the probability of observing at least one significant result from a number of tests by chance alone, revealed that only the deficiency of heterozygotes at Pgm and Mpi loci was significant at the table-wide 95% level. Since post-collection mortality was <3%, these heterozygote deficits must have existed at the time of collection. The conclusion drawn is that heterozygote deficiencies in mussels are generated during the larval stage or at early settlement.
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Dooner, H. K., e J. L. Kermicle. "THE TRANSPOSABLE ELEMENT Ds AFFECTS THE PATTERN OF INTRAGENIC RECOMBINATION AT THE bz AND R LOCI IN MAIZE". Genetics 113, n.º 1 (1 de maio de 1986): 135–43. http://dx.doi.org/10.1093/genetics/113.1.135.
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ABSTRACT Insertion of the transposable element Ds into either the bz or R locus affects intragenic recombination in various ways. We have examined here one aspect of this problem; namely, the distribution of flanking markers among intragenic recombinations produced by different types of heterozygotes carrying Ds insertion mutations. Heteroallelic combinations of a Ds insertion mutation and a mutation borne on a structurally normal chromosome generate a majority of intragenic recombinants of a crossover type. In contrast to this, most intragenic recombinants obtained from heterozygotes between two different Ds insertion mutations have a parental arrangement of outside markers. Therefore, the resolution of the recombination intermediate would appear to depend on the nature of the mutations in the heterozygote.
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Motojima, Masaru, Sho Tanimoto, Masato Ohtsuka, Taiji Matsusaka, Tsutomu Kume e Koichiro Abe. "Characterization of Kidney and Skeleton Phenotypes of Mice Double Heterozygous for Foxc1 and Foxc2". Cells Tissues Organs 201, n.º 5 (2016): 380–89. http://dx.doi.org/10.1159/000445027.
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Foxc1 and Foxc2 play key roles in mouse development. Foxc1 mutant mice develop duplex kidneys with double ureters, and lack calvarial and sternal bones. Foxc2 null mice have been reported to have glomerular abnormalities in the kidney and axial skeletal anomalies. Expression patterns of Foxc1 and Foxc2 overlap extensively and are believed to have interactive roles. However, cooperative roles of these factors in glomerular and skeletal development are unknown. Therefore, we examined the kidneys and skeleton of mice that were double heterozygous for Foxc1 and Foxc2. Double heterozygotes were generated by mating single heterozygotes for Foxc1 and Foxc2. Newborn double heterozygous mice showed many anomalies in the kidney and urinary tract resembling Foxc1 phenotypes, including duplex kidneys, double ureters, hydronephrosis and mega-ureter. Some mice had hydronephrosis alone. In addition to these macroscopic anomalies, some mice had abnormal glomeruli and disorganized glomerular capillaries observed in Foxc2 phenotypes. Interestingly, these mice also showed glomerular cysts not observed in the single-gene knockout of either Foxc1 or Foxc2 but observed in conditional knockout of Foxc2 in the kidney. Serial section analysis revealed that all cystic glomeruli were connected to proximal tubules, precluding the possibility of atubular glomeruli resulting in cyst formation. Dorsally opened vertebral arches and malformations of sternal bones in the double heterozygotes were phenotypes similar to Foxc1 null mice. Absent or split vertebral bodies in the double heterozygotes were phenotypes similar to Foxc2 null mice, whilst hydrocephalus noted in the Foxc1 phenotype was not observed. Thus, Foxc1 and Foxc2 have a role in kidney and axial skeleton development. These transcription factors might interact in the regulation of the embryogenesis of these organs.
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Torpy, David J., Anthony W. Bachmann, Jeffrey E. Grice, Stephen P. Fitzgerald, Patrick J. Phillips, Judith A. Whitworth e Richard V. Jackson. "Familial Corticosteroid-Binding Globulin Deficiency Due to a Novel Null Mutation: Association with Fatigue and Relative Hypotension". Journal of Clinical Endocrinology & Metabolism 86, n.º 8 (1 de agosto de 2001): 3692–700. http://dx.doi.org/10.1210/jcem.86.8.7724.
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Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue −12 of the procorticosteroid-binding globulin molecule (c.121G→A). Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 ± 1.3 μg/ml (reference range, 30–52 μg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 μg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue. Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 ± 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 ± 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10. Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 ± 2.5 in 18 adults with the mutation vs. 4.2 ± 1.5 in 23 healthy controls (P < 0.0001). Compound heterozygosity for both mutations resulted in plasma cortisol levels comparable to those in null homozygotes. Abnormal corticosteroid-binding globulin concentrations or binding affinity may lead to the misdiagnosis of isolated ACTH deficiency. The mechanism of the association between fatigue and relative hypotension is not established by these studies. As idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of corticosteroid-binding globulin may be pathogenic.
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Alcalay, R. N., A. Siderowf, R. Ottman, E. Caccappolo, H. Mejia-Santana, M. X. Tang, L. Rosado et al. "Olfaction in Parkin heterozygotes and compound heterozygotes: The CORE-PD study". Neurology 76, n.º 4 (29 de dezembro de 2010): 319–26. http://dx.doi.org/10.1212/wnl.0b013e31820882aa.
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Ying, Ying, Xiao-Ming Liu, Amy Marble, Kirstie A. Lawson e Guang-Quan Zhao. "Requirement of Bmp8b for the Generation of Primordial Germ Cells in the Mouse". Molecular Endocrinology 14, n.º 7 (1 de julho de 2000): 1053–63. http://dx.doi.org/10.1210/mend.14.7.0479.
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Abstract In the mouse embryo, the generation of primordial germ cells (PGCs) from the epiblast requires a bone morphogenetic protein-4 (BMP4) signal from the adjacent extraembryonic ectoderm. In this study, we report that Bmp8b, a member of the Gbb-60A class of the BMP superfamily, is expressed in the extraembryonic ectoderm in pregastrula and gastrula stage mouse embryos and is required for PGC generation. A mutation in Bmp8b on a mixed genetic background results in the absence of PGCs in 43% null mutant embryos and severe reduction in PGC number in the remainder. The heterozygotes are unaffected. On a largely C57BL/6 background, Bmp8b null mutants completely lack PGCs, and Bmp8b heterozygotes have a reduced number of PGCs. In addition, Bmp8b homozygous null embryos on both genetic backgrounds have a short allantois, and this organ is missing in some more severe mutants. Since Bmp4 heterozygote embryos have reduced numbers of PGCs, we used a genetic approach to generate double-mutant embryos to study interactions of Bmp8b and Bmp4. Embryos that are double heterozygotes for the Bmp8b and Bmp4 mutations have similar defects in PGC number as Bmp4 heterozygotes, indicating that the effects of the two BMPs are not additive. These findings suggest that BMP4 and BMP8B function as heterodimers and homodimers in PGC specification in the mouse.
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Kropp, Peter A., Jennifer C. Dunn, Bethany A. Carboneau, Doris A. Stoffers e Maureen Gannon. "Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability". American Journal of Physiology-Endocrinology and Metabolism 314, n.º 4 (1 de abril de 2018): E308—E321. http://dx.doi.org/10.1152/ajpendo.00260.2017.
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The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.
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Kotchetkoff, Elaine Cristina de Almeida, Fabíola Isabel Suano de Souza, Fernando Luiz Affonso Fonseca, Sonia Hix, Sergio Aron Ajzen, David Carlos Shigueoka, Beatriz Tavares Costa Carvalho e Roseli Oselka Saccardo Sarni. "Assessing cardiovascular risk in ATM heterozygotes". Revista da Associação Médica Brasileira 64, n.º 2 (fevereiro de 2018): 148–53. http://dx.doi.org/10.1590/1806-9282.64.02.148.
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Summary Objective: To evaluate the carotid intima-media complex (CIMC) thickness and lipid metabolism biomarkers associated with cardiovascular risk (CR) in parents of patients with ataxia-telangiectasia and verify an association with gender. Method: A cross-sectional and controlled study with 29 ATM heterozygotes and 14 healthy controls. Biochemical tests and CIMC thickness measurement were performed. Results: The mean CIMC measurement in heterozygous ATM was 0.72 ± 0.1 mm (minimum: 0.5 mm and maximum: 1.0 mm). Noticed high percentage of amounts above 75 percentile compared to the population referential (16 [76.2%]), without any significant statistical differences between the female and the male gender (11/15 [73.3%] vs. 5/6 [83.3%]; p=0.550). The comparison between heterozygous and controls, stratified by gender, showed that in heterozygous ATMs, women had higher concentrations of HDL-c compared to men, as well as higher values of hs-CRP in relation to the control women. In heterozygous ATMs, stratified by gender, the correlation between HDL-c and hs-CRP was inversely proportional and stronger among women, with a tendency to statistical significance. Conclusion: Heterozygous ATMs did not differ from controls in relation to the biomarkers studied related to CR. However, most of them presented increased CIMC, independent predictor of death, risk for myocardial infarction and stroke, compared to the referential for the same age group. This finding suggests CR in the heterozygous ATM and shows to the need to monitor CIMC thickness and nutritional orientations.
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Marx, Stephen J., e Ninet Sinaii. "Neonatal Severe Hyperparathyroidism: Novel Insights From Calcium, PTH, and the CASR Gene". Journal of Clinical Endocrinology & Metabolism 105, n.º 4 (28 de novembro de 2019): 1061–78. http://dx.doi.org/10.1210/clinem/dgz233.
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Abstract Context Neonatal severe hyperparathyroidism (NSHPT) is rare and potentially lethal. It is usually from homozygous or heterozygous germline-inactivating CASR variant(s). NSHPT shows a puzzling range of serum calcium and parathyroid hormone (PTH) levels. Optimal therapy is unclear. Evidence acquisition We categorized genotype/phenotype pairings related to CASRs. For the 2 pairings in NSHPT, each of 57 cases of neonatal severe hyperparathyroidism required calcium, PTH, upper normal PTH, and dosage of a germline pathogenic CASR variant. Evidence synthesis Homozygous and heterozygous NSHPT are 2 among a spectrum of 9 genotype/phenotype pairings relating to CASRs and NSHPT. For the 2 NSHPT pairings, expressions differ in CASR allelic dosage, CASR variant severity, and sufficiency of maternofetal calcium fluxes. Homozygous dosage of CASR variants was generally more aggressive than heterozygous. Among heterozygotes, high-grade CASR variants in vitro were more pathogenic in vivo than low-grade variants. Fetal calcium insufficiency as from maternal hypoparathyroidism caused fetal secondary hyperparathyroidism, which persisted and was reversible in neonates. Among NSHPT pairings, calcium and PTH were higher in CASR homozygotes than in heterozygotes. Extreme hypercalcemia (above 4.5 mM; normal 2.2–2.6 mM) is a robust biomarker, occurring only in homozygotes (83% of that pairing). It could occur during the first week. Conclusions In NSHPT pairings, the homozygotes for pathogenic CASR variants show higher calcium and PTH levels than heterozygotes. Calcium levels above 4.5 mM among NSHPT are frequent and unique only to most homozygotes. This cutoff supports early and robust diagnosis of CASR dosage. Thereby, it promotes definitive total parathyroidectomy in most homozygotes.
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Gallant, E. M., J. R. Mickelson, B. D. Roggow, S. K. Donaldson, C. F. Louis e W. E. Rempel. "Halothane-sensitivity gene and muscle contractile properties in malignant hyperthermia". American Journal of Physiology-Cell Physiology 257, n.º 4 (1 de outubro de 1989): C781—C786. http://dx.doi.org/10.1152/ajpcell.1989.257.4.c781.
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Malignant hyperthermia (MH) results from the presence of the halothane-sensitivity gene and is characterized by abnormalities in muscle function. Populations of genetically defined pigs were used to determine the in vivo and in vitro expression of this gene in both the homozygous and the heterozygous condition. On exposure to halothane, isolated muscle bundles from the homozygous halothane-sensitive pigs exhibited decreased tetanus tension and increased tetanus half-relaxation time and contracture and were clearly distinguished from homozygous normal muscles. The heterozygous and homozygous normal muscles were similar in contractile responses except for the occurrence of halothane-induced contractures in the heterozygotes. The heterozygous halothane-negative pigs did not exhibit the characteristic signs of an MH episode in response to halothane succinylcholine, although some metabolic responses were significantly altered (e.g., increased venous partial pressure of CO2 and arterial and venous K+ concentration). Thus the heterozygous pigs were not MH susceptible but did represent a phenotype distinct from the homozygous normal pigs both in vitro and in vivo. These data provide the first convincing evidence for the expression of the halothane-sensitivity gene in heterozygotes.
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Felice, Alexander, Joseph Borg, Wilma Cassar, Ruth Galdies, Monica Pizzuto, Maryrose Caruana e Christian Scerri. "Hb F Malta I in Association with Hb F Sardinia (AyT) and Hb Valletta in Heterozygotes: Quantification of the Six Globins Suggests Developmental Control of the XMN-I Site and Interplay with the (AT)xTy Sequence in Connection with Globin Gene Switching." Blood 108, n.º 11 (16 de novembro de 2006): 3830. http://dx.doi.org/10.1182/blood.v108.11.3830.3830.
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Abstract Although the precise biochemical mechanisms of globin gene switching remain elusive, considerable insight is gained by in vivo expression profiling through quantification of the hemoglobin / globin phenotype of informative heterozygosities and homozygosities / compound heterozygosities in the context of specific regulatory DNA sequence diversity such as the XMN-I or the [(AT)xTy] sequence polymorphisms. The quantification of normal and abnormal globins of Hb F Malta-I (or a2b2, 117(G19)His>Arg) heterozygotes which are in tight linkage disequilibrium with Hb Valletta (or a2b2 287(f3)Thr>Pro) i.e. Gyo, GyFMalta-I, AyI, bV and bA together with extensive haplotyping of homozygotes and heterozygotes including the XMN-I dimorphism in the Gy promoter and the (AT)xTy polymorphism (BP1 binding site) 5′ to the b globin genes had suggested that the XMN-I dimorphism was largely inactive in the normal newborn. In contrast the Hb F levels and the proportion of Gy globin in anemic adult beta-thalassemia homozygotes and compound heterozygotes differed significantly, depending on the XMN-I genotype (TT, TC or CC) Here, we document the occurrence of seven newborn who were heterozygous at three globin loci permitting quantification by reverse phase liquid chromatography of the six globin products; Gyo, GyFMalta-I, AyI, AyT, bV and bA in the context of genotypic variation at the XMN-I and (AT)xTy sequences. The data were compared with those of newborn HbF-Malta-I-Hb-Valletta heterozygotes and anemic adult beta thalassemia homozygotes / compound heterozygotes. The globin quantification together with haplotype data were analysed using the general linear model (two-way ANOVA) by SPSS version 12. The data excluded significant effect of the XMN-I dimorphism alone on relative y/b globin gene expression in the newborn. On the other hand, the (AT)xTy polymorphism with BP1 binding sites of 21 [(AT)7T7], 23 [(AT)9T5], or 25 [(AT)11T3], nucleotides in trans over-ride XMN-I. In contrast, it is the XMN-I dimorphism that over-rides the (AT)xTy diversity in the anemic adult beta thalassemia homozygotes or compound heterozygotes. The GyFMalta-I/Gyo ratio of the newborn heterozygotes with Hb F Malta-I and the AyT/AyI ratio of the newborn heterozygotes with HbF-Malta-I and HbF-Sardinia suggested that the developmental regulation of the XMN-I site may be subject to cis/trans interplay with the (AT)xTy sequences.
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Lozano, R., C. Ruiz Rejón e M. Ruiz Rejón. "Interchange polymorphism in natural populations of Allium paniculatum L. (Liliaceae): nature, frequency, effects, and mechanism of maintenance". Canadian Journal of Genetics and Cytology 28, n.º 3 (1 de junho de 1986): 348–57. http://dx.doi.org/10.1139/g86-052.
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A reciprocal translocation was found with a high frequency (average 44.44%) in four natural populations of Allium paniculatum L. (Liliaceae) from the South of Spain. The chromosomes involved are 1 and 7. The translocation is reciprocal and unequal. Chiasma frequency in the chromosomes not involved in the interchange is not affected, but chiasma frequency is decreased in the translocated chromosomes in the heterozygotes. As a satellite chromosome is involved in the interchange, the nucleolus is associated with the quadrivalent and the pattern of nucleolus formation is changed in heterozygotes, which have a lower mean number of nucleoli [Formula: see text] than homozygous standard individuals [Formula: see text]. The spontaneous mutation rate for interchanges during the early stages of microsporogenesis is high (μ = 1.08 × 10−2). No interchange homozygotes were found in any of the four populations analyzed. Furthermore, a comparative analysis of heterozygous (HT) and homozygous standard (HM) individuals in two populations demonstrated that homozygous standard plants show, on the whole, higher fitness than the heterozygotes. This can be attributed to a greater egg cell fertility and seed set. The possible causes of maintenance are discussed: the interchange in A. paniculatum is probably not maintained by overdominance for generative reproductive characters, nor by a mutation–selection equilibrium. One possibility, that heterozygotes have superior vegetative reproduction, still remains open for future investigation.Key words: Allium paniculatum, interchange polymorphism, fitness.
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West, John D., e Jean H. Flockhart. "Non-additive inheritance of glucose phosphate isomerase activity in mice heterozygous at the Gpi-1s structural locus". Genetical Research 54, n.º 1 (agosto de 1989): 27–36. http://dx.doi.org/10.1017/s0016672300028342.
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SummaryThe activity of blood glucose phosphate isomerase (GPI-1) in mice heterozygous for various alleles at the Gpi-1s structural locus (heterozygotes a/b, a/c and b/c) was significantly higher than expected, on the basis of additive inheritance, from the levels in parental homozygotes. Moreover, the GPI-1 activity was higher in a/b heterozygotes than in either parent (heterosis). Studies of heat stability with kidney homogenates revealed that the relative stabilities of GPI-1 dimers was AA > AB > BB > AC ≥ BC > CC. Differences in dimer stabilities in vivo would affect the total GPI-1 levels in heterozygotes and could account for non-additive inheritance but would be insufficient to explain heterosis for GPI-1 activity. Other possible contributing factors include unequal production or stability of monomers, or higher catalytic activity of heterodimers. Monomers could also associate non-randomly but this would not be sufficient to explain heterosis. It is clear that non-additive inheritance patterns may be produced by variants of either structural or regulatory genes.
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Pittschieler, Klaus. "Heterozygotes and liver involvement". Acta Paediatrica 83, s393 (fevereiro de 1994): 21–23. http://dx.doi.org/10.1111/j.1651-2227.1994.tb13202.x.
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Mitchell, SC. "Trimethylaminuria: susceptibility of heterozygotes". Lancet 354, n.º 9196 (dezembro de 1999): 2164–65. http://dx.doi.org/10.1016/s0140-6736(05)77067-7.
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Dechant, Michael, Thomas Poellot, Ulrich Kunzendorf e Thomas Valerius. "Heterogeneous Expression of the 158V and 158F Alleles in FcγRIIIA Heterozygous Donors." Blood 104, n.º 11 (16 de novembro de 2004): 1362. http://dx.doi.org/10.1182/blood.v104.11.1362.1362.
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Abstract Recent clinical studies demonstrated that a bi-allelic polymorphism in the human FCGRIIIA gene critically determines the clinical outcome of rituximab therapy in certain hematologic malignancies and in autoimmune diseases. Thus, patients homozygous for the 158V allele of the FcγRIIIa receptor demonstrated significantly better response rates to rituximab therapy compared to homozygous 158F donors. However, confliciting data were reported for heterozygous patients - which account for approximately 45 % of the investigated population. Furthermore, most of the in vitro reports about functional effects of this polymorphism did not address the function of 158V/F heterozygotes. In all these studies, genomic DNA was used for allotyping of the FCGRIIIA 158V/F polymorphism. Thus, these studies were not set up to investigate potential allele- specific differences at mRNA or protein levels, which were demonstrated for several other NK cell- related genes. Therefore, we were interested to analyze receptor expression and function in 158V/F heterozygous donors in more detail. First, we established FCGRIIIA allotyping at the mRNA level. Thus, isolated mRNA was reversely transcribed, PCR amplified and sequenced using BigDye terminator mix. Results from homozygous donors were consistent and homogeneous, whereas sequencing profiles from heterozygotes appeared heterogeneous. Some 158V/F heterozygotes demonstrated similar expression of both alleles, whereas sequencing profiles in others were almost similar to either homozygous 158V/V or homozygous 158F/F donors. Next, we analyzed the quantitative expression of the corresponding proteins by immunofluorescence experiments with antibodies 3G8 and MEM-154. While 3G8 binds similarly to both allelic forms of FcγRIIIa, MEM-154 preferentially recognizes the 158V allele, as confirmed by immunofluorescence studies with FcγRIIIa 158F or 158V transfected cell lines. These experiments again demonstrated that FcγRIIIA 158V/F heterozygous donors are a heterogeneous group - with 158V protein levels ranging from similar to 158F/F homozygotes to similar to 158V/V homozygous donors. Furthermore, we investigated whether 158V expression levels have functional implications in classical 51Cr- release assays against ARH-77 B cells. We used isolated NK cells as effector cells, and rituximab as sensitizing antibody. Effector cells were isolated from matched sets of FCγRIIIA allotyped donors to directly compare 158V/V or 158F/F homozygotes with 158V/F heterozygotes. As described by others, we observed statistically significant differences between 158V/V and 158F/F homozygous donors at suboptimal antibody concentrations. Interestingly, NK cells from 158F/V heterozygous donors, which appeared similar by sequencing profiles and by immunofluorescence studies to effector cells from 158V/V homozygotes, also demonstrated killing levels similar to those from 158V/V homozygous donors. In conclusion, our data demonstrate that donors heterozygous for FcγRIIIA at position 158 are a heterogeneous population - potentially explaining controversial data published about 158F/V heterozygotes in clinical studies. In order to further assess the biological impact of our results, clinical trials may address whether FcγRIIIA 158V expression levels will correlate with clinical responses to rituximab therapy. These studies could help to predict which patients may optimally benefit from rituximab therapy.