Zeitschriftenartikel: „Microsatellite disorders“

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Richard, Guy-Franck. „The Startling Role of Mismatch Repair in Trinucleotide Repeat Expansions“. Cells 10, Nr. 5 (26.04.2021): 1019. http://dx.doi.org/10.3390/cells10051019.

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Trinucleotide repeats are a peculiar class of microsatellites whose expansions are responsible for approximately 30 human neurological or developmental disorders. The molecular mechanisms responsible for these expansions in humans are not totally understood, but experiments in model systems such as yeast, transgenic mice, and human cells have brought evidence that the mismatch repair machinery is involved in generating these expansions. The present review summarizes, in the first part, the role of mismatch repair in detecting and fixing the DNA strand slippage occurring during microsatellite replication. In the second part, key molecular differences between normal microsatellites and those that show a bias toward expansions are extensively presented. The effect of mismatch repair mutants on microsatellite expansions is detailed in model systems, and in vitro experiments on mismatched DNA substrates are described. Finally, a model presenting the possible roles of the mismatch repair machinery in microsatellite expansions is proposed.

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Avvaru, Akshay Kumar, Deepak Sharma, Archana Verma, Rakesh K. Mishra und Divya Tej Sowpati. „MSDB: a comprehensive, annotated database of microsatellites“. Nucleic Acids Research 48, Nr. D1 (10.10.2019): D155—D159. http://dx.doi.org/10.1093/nar/gkz886.

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Abstract Microsatellites are short tandem repeats of 1–6 nucleotide motifs, studied for their utility as genome markers and in forensics. Recent evidence points to the role of microsatellites in important regulatory functions, and their length polymorphisms at coding regions are linked to various neurodegenerative disorders in humans. Microsatellites show a taxon-specific enrichment in eukaryotic genomes, and their evolution remains poorly understood. Though other databases of microsatellites exist, they fall short on several fronts. MSDB (MicroSatellite DataBase) is a collection of >4 billion microsatellites from 37 680 genomes presented in a user-friendly web portal for easy, interactive analysis and visualization. This is by far the most comprehensive, annotated, updated database to access and analyze microsatellite data of multiple species. The features of MSDB enable users to explore the data as tables that can be filtered and exported, and also as interactive charts to view and compare the data of multiple species simultaneously. Its modularity and architecture permit seamless updates with new data, making it a powerful tool and useful resource to researchers working on this important class of DNA elements, particularly in context of their evolution and emerging roles in genome organization and gene regulation.

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Ranum, Laura P. W., und John W. Day. „Dominantly inherited, non-coding microsatellite expansion disorders“. Current Opinion in Genetics & Development 12, Nr. 3 (Juni 2002): 266–71. http://dx.doi.org/10.1016/s0959-437x(02)00297-6.

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Volpe, G., B. Gamberi, C. Pastore, A. Roetto, M. Pautasso, G. Parvis, C. Camaschella, U. Mazza, G. Saglio und G. Gaidano. „Analysis of microsatellite instability in chronic lymphoproliferative disorders“. Annals of Hematology 72, Nr. 2 (Februar 1996): 67–71. http://dx.doi.org/10.1007/bf00641310.

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Volpe, G., B. Gamberi, C. Pastore, A. Roetto, M. Pautasso, G. Parvis, C. Camaschella, U. Mazza, G. Saglio und G. Gaidano. „Analysis of microsatellite instability in chronic lymphoproliferative disorders“. Annals of Hematology 72, Nr. 2 (01.02.1996): 67–71. http://dx.doi.org/10.1007/s002770050139.

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Poggi, Lucie, Lisa Emmenegger, Stéphane Descorps-Declère, Bruno Dumas und Guy-Franck Richard. „Differential efficacies of Cas nucleases on microsatellites involved in human disorders and associated off-target mutations“. Nucleic Acids Research 49, Nr. 14 (07.07.2021): 8120–34. http://dx.doi.org/10.1093/nar/gkab569.

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Abstract Microsatellite expansions are the cause of >20 neurological or developmental human disorders. Shortening expanded repeats using specific DNA endonucleases may be envisioned as a gene editing approach. Here, we measured the efficacy of several CRISPR–Cas nucleases to induce recombination within disease-related microsatellites, in Saccharomyces cerevisiae. Broad variations in nuclease performances were detected on all repeat tracts. Wild-type Streptococcus pyogenes Cas9 (SpCas9) was more efficient than Staphylococcus aureus Cas9 on all repeats tested, except (CAG)33. Cas12a (Cpf1) was the most efficient on GAA trinucleotide repeats, whereas GC-rich repeats were more efficiently cut by SpCas9. The main genetic factor underlying Cas efficacy was the propensity of the recognition part of the sgRNA to form a stable secondary structure, independently of its structural part. This suggests that such structures form in vivo and interfere with sgRNA metabolism. The yeast genome contains 221 natural CAG/CTG and GAA/CTT trinucleotide repeats. Deep sequencing after nuclease induction identified three of them as carrying statistically significant low frequency mutations, corresponding to SpCas9 off-target double-strand breaks.

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Shoab Mansuri, Mohmmad, Mala Singh und Munira Jariwala. „Investigating the Association of Poly (ADP-Ribose) Polymerase-1 (PARP-1) and Nuclear Factor-κB (NF-κB) Polymorphisms with Vitiligo Susceptibility“. International Journal of Research and Review 9, Nr. 10 (17.10.2022): 277–85. http://dx.doi.org/10.52403/ijrr.20221032.

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Background: Poly (ADP-ribose) polymerase-1 (PARP-1) is a co-activator of nuclear factor-κB (NF-κB) and is also strongly activated by DNA damage. PARP has also been found to be associated with several autoimmune disorders. Vitiligo is a polygenic, multifactorial, acquired skin disorder caused due to loss of epidermal melanocytes. Among others, genetic and immunological factors are associated with vitiligo pathogenesis. Aim: To investigate the association of PARP1 exon 17 (rs1136410; V762A) and promoter CA microsatellite repeat (rs1136410) polymorphisms, and NF-κB promoter -94 indelATTG (rs28362491) polymorphism with vitiligo pathogenesis in Gujarat population. Methods: Genotyping of PARP1 17T/C (rs5030870) polymorphism was done by PCR-RFLP.PARP1 CA microsatellite and NF-κB-94 indel (rs28362491) polymorphisms were genotyped by Real-Time PCR. Anti-PARP antibody levels were assessed by ELISA. Results: The results suggested no significant difference in allele and genotype frequencies of PARP1 17 T/C (p=0.5094 and p=0.4201, respectively), PARP1 CA microsatellite polymorphisms (p=0.9519 and p=0.9338, respectively) and NF-κB-94 ATTG indel polymorphism (p=0.1482 and p=0.3784, respectively) in patients as compared to controls. Conclusion: This study suggests no association of PARP1 17 T/C, PARP1 CA microsatellite and NF-κB-94 ATTG indel polymorphisms with vitiligo susceptibility in Gujarat population. Additionally, anti-PARP1 antibody levels were not significantly different among patients and controls. These findings suggest the need for additional studies to explore the role of PARP1 in vitiligo pathogenesis. Keywords: Vitiligo, poly (ADP-ribose) polymerase-1(PARP-1), nuclear factor-κB (NF-κB), polymorphisms, Autoimmunity

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Echeverria, Gloria V., und Thomas A. Cooper. „RNA-binding proteins in microsatellite expansion disorders: Mediators of RNA toxicity“. Brain Research 1462 (Juni 2012): 100–111. http://dx.doi.org/10.1016/j.brainres.2012.02.030.

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Hayward, Bruce E., Peter J. Steinbach und Karen Usdin. „A point mutation in the nuclease domain of MLH3 eliminates repeat expansions in a mouse stem cell model of the Fragile X-related disorders“. Nucleic Acids Research 48, Nr. 14 (03.07.2020): 7856–63. http://dx.doi.org/10.1093/nar/gkaa573.

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Abstract The Fragile X-related disorders (FXDs) are Repeat Expansion Diseases, genetic disorders that result from the expansion of a disease-specific microsatellite. In those Repeat Expansion Disease models where it has been examined, expansion is dependent on functional mismatch repair (MMR) factors, including MutLγ, a heterodimer of MLH1/MLH3, one of the three MutL complexes found in mammals and a minor player in MMR. In contrast, MutLα, a much more abundant MutL complex that is the major contributor to MMR, is either not required for expansion or plays a limited role in expansion in many model systems. How MutLγ acts to generate expansions is unclear given its normal role in protecting against microsatellite instability and while MLH3 does have an associated endonuclease activity, whether that contributes to repeat expansion is uncertain. We show here, using a gene-editing approach, that a point mutation that eliminates the endonuclease activity of MLH3 eliminates expansions in an FXD mouse embryonic stem cell model. This restricts the number of possible models for repeat expansion and supports the idea that MutLγ may be a useful druggable target to reduce somatic expansion in those disorders where it contributes to disease pathology.

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Grespi, Valentina, Cecilia Caprera, Claudia Ricciolini, Ilaria Bicchi, Gianmarco Muzi, Matteo Corsi, Stefano Ascani, Angelo Luigi Vescovi und Maurizio Gelati. „Human neural stem cells drug product: Microsatellite instability analysis“. PLOS ONE 17, Nr. 8 (30.08.2022): e0273679. http://dx.doi.org/10.1371/journal.pone.0273679.

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Introduction In central nervous system neurodegenerative disorders, stem cell-based therapies should be considered as a promising therapeutic approach. The safe use of human Neural Stem Cells (hNSCs) for the treatment of several neurological diseases is currently under evaluation of phase I/II clinical trials. Clinical application of hNSCs require the development of GMP standardized protocols capable of generating high quantities of reproducible and well characterized stem cells bearing stable functional and genetic properties. Aim The aim of this study was to evaluate possible instabilities or modifications of the microsatellite loci in different culture passages because high culture passages represent an in vitro replicative stress leading to senescence. Experimental method: The hNSCs were characterized at different culture time points, from passage 2 to passage 25, by genetic typing at ten microsatellite loci. Conclusion We showed that genetic stability at microsatellite loci is maintained by the cells even at high passages adding a further demonstration of the safety of our hNSCs GMP culture method.

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Castelli, Lydia M., Wan-Ping Huang, Ya-Hui Lin, Kung-Yao Chang und Guillaume M. Hautbergue. „Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders“. Biochemical Society Transactions 49, Nr. 2 (17.03.2021): 775–92. http://dx.doi.org/10.1042/bst20200690.

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Repeat-associated non-AUG (RAN) translation was discovered in 2011 in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1). This non-canonical form of translation occurs in all reading frames from both coding and non-coding regions of sense and antisense transcripts carrying expansions of trinucleotide to hexanucleotide repeat sequences. RAN translation has since been reported in 7 of the 53 known microsatellite expansion disorders which mainly present with neurodegenerative features. RAN translation leads to the biosynthesis of low-complexity polymeric repeat proteins with aggregating and cytotoxic properties. However, the molecular mechanisms and protein factors involved in assembling functional ribosomes in absence of canonical AUG start codons remain poorly characterised while secondary repeat RNA structures play key roles in initiating RAN translation. Here, we briefly review the repeat expansion disorders, their complex pathogenesis and the mechanisms of physiological translation initiation together with the known factors involved in RAN translation. Finally, we discuss research challenges surrounding the understanding of pathogenesis and future directions that may provide opportunities for the development of novel therapeutic approaches for this group of incurable neurodegenerative diseases.

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Cleary, John Douglas, und Laura PW Ranum. „Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders“. Current Opinion in Genetics & Development 26 (Juni 2014): 6–15. http://dx.doi.org/10.1016/j.gde.2014.03.002.

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Ginter, E. K., und S. N. Illarioshkin. „ADVANCE OF GENETICS AND GENOMICS IN NEUROLOGY“. Annals of the Russian academy of medical sciences 67, Nr. 8 (11.08.2012): 14–20. http://dx.doi.org/10.15690/vramn.v67i8.344.

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Studies of genomic basis of neurological disorders is very actual in view of their high population prevalence, severe course, serious patients’ disability, and progressive mental and physical de-adaptation. In the paper, problems of genetic heterogeneity of hereditary neurological disorders and character of the respective genetic burden in the regions of Russian Federation are discussed in detail, a ‘dynamic’ type of mutations (increase in copy number of microsatellite repeats) attributable to many neurodegenerative diseases is analyzed, and achievements of Russian researchers in the identification of genes for hereditary neurological disorders and in the realization of pilot protocols of gene therapy are presented. Problems related to studies of genetic predisposition to common multifactorial diseases of the nervous system are discussed.

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Zu, Tao, Brian Gibbens, Noelle S. Doty, Mário Gomes-Pereira, Aline Huguet, Matthew D. Stone, Jamie Margolis et al. „Non-ATG–initiated translation directed by microsatellite expansions“. Proceedings of the National Academy of Sciences 108, Nr. 1 (20.12.2010): 260–65. http://dx.doi.org/10.1073/pnas.1013343108.

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Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.

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Nakamura, Akie, Koji Muroya, Hiroko Ogata-Kawata, Kazuhiko Nakabayashi, Keiko Matsubara, Tsutomu Ogata, Kenji Kurosawa, Maki Fukami und Masayo Kagami. „A case of paternal uniparental isodisomy for chromosome 7 associated with overgrowth“. Journal of Medical Genetics 55, Nr. 8 (17.02.2018): 567–70. http://dx.doi.org/10.1136/jmedgenet-2017-104986.

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BackgroundPaternal uniparental disomy for chromosome 7 (upd(7)pat) is extremely rare, and only four cases have been previously reported. As these cases were accompanied by autosomal-recessive disorders which are likely to be involved in growth restriction, the relevance of upd(7)pat to the overgrowth phenotype remains unclear. Here we describe one case of upd(7)pat with no additional genetic diseases, which may answer the question.MethodsA 5-year-old Japanese boy presented with a tall stature of unknown causes. To detect the genetic cause of the tall stature, we performed Sanger sequencing, targeted resequencing, comparative genomic hybridisation and single-nucleotide polymorphism (SNP) array analyses, methylation analysis and microsatellite analysis.ResultsWe could not detect pathogenic variants in causative genes for overgrowth syndrome or apparent copy number alterations. DNA methylation analysis revealed hypomethylation at the GRB10, PEG1 and PEG10 differentially methylated regions. SNP array and microsatellite analyses suggested paternal uniparental isodisomy for chromosome 7. Furthermore, we could not identify homozygous mutations of known causative genes for inherited disorders on chromosome 7.ConclusionWe report the first case of upd(7)pat with an overgrowth phenotype.

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Asimakopoulos, FA, JG Gilbert, MA Aldred, TC Pearson und AR Green. „Interstitial deletion constitutes the major mechanism for loss of heterozygosity on chromosome 20q in polycythemia vera“. Blood 88, Nr. 7 (01.10.1996): 2690–98. http://dx.doi.org/10.1182/blood.v88.7.2690.bloodjournal8872690.

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An acquired deletion of the long arm of chromosome 20 is a recurrent abnormality in myeloproliferative disorders, particularly polycythemia vera and myelodysplastic syndromes. The association of 20q deletions with myeloid “stem cell” disorders suggests that the deletions mark the site of one or more genes, loss or inactivation of which plays a role in the regulation of normal hematopoietic progenitors. We have recently performed a detailed molecular analysis of 20q deletions in peripheral blood (PB) granulocytes and defined a commonly deleted region of 16 to 21 centimorgan (cM). To further reduce the size of the common deleted region we have searched for small deletions or mitotic recombination events, neither of which would be detected by conventional cytogenetics. We have studied 48 patients with polycythemia vera and four patients with idiopathic myelofibrosis. In each case, cytogenetic analysis had either failed or had shown no abnormalities of chromosome 20. Seventeen microsatellite markers that span the common deleted region were used to search for loss of heterozygosity in granulocyte DNA. No instance of microsatellite instability was observed in a total of 880 comparisons of granulocyte and T-cell DNA. Granulocyte DNA from four patients exhibited allele loss on 20q. In each case the allele loss was caused by an interstitial deletion because heterozygosity at distal markers was retained and because quantitative Southern blotting demonstrated hemizygosity. Loss of heterozygosity in PB granulocytes would be masked by the presence of significant numbers of normal granulocytes not derived from the malignant clone. Therefore, the human androgen receptor assay (HUMARA) was used to determine granulocyte clonality. In 21 of 27 informative female patients the majority of the granulocytes were clonally derived. In 5 patients the granulocytes appeared polyclonal and in 1 patient unilateral X inactivation was observed in both granulocytes and T cells. These results show that, in the vast majority of patients presented here, the failure to detect loss of heterozygosity cannot be attributed to the presence of normal polyclonal granulocytes. Our results therefore show that allele loss on chromosome 20q in polycythemia vera does not commonly involve mitotic recombination or chromosome loss and that microsatellite instability is a rare event in this disorder.

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Hammock, Elizabeth A. D., und Larry J. Young. „Oxytocin, vasopressin and pair bonding: implications for autism“. Philosophical Transactions of the Royal Society B: Biological Sciences 361, Nr. 1476 (06.11.2006): 2187–98. http://dx.doi.org/10.1098/rstb.2006.1939.

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Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a species-specific repetitive element, or ‘microsatellite’, in the 5′ regulatory region of the gene encoding V1aR ( avpr1a ). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders.

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Bender, Chelsea, Elizabeth Geena Woo, Bin Guan, Ehsan Ullah, Eric Feng, Amy Turriff, Santa J. Tumminia, Paul A. Sieving, Catherine A. Cukras und Robert B. Hufnagel. „Predominant Founder Effect among Recurrent Pathogenic Variants for an X-Linked Disorder“. Genes 13, Nr. 4 (12.04.2022): 675. http://dx.doi.org/10.3390/genes13040675.

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For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.

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Asimakopoulos, FA, TL Holloway, EP Nacheva, MA Scott, P. Fenaux und AR Green. „Detection of chromosome 20q deletions in bone marrow metaphases but not peripheral blood granulocytes in patients with myeloproliferative disorders or myelodysplastic syndromes“. Blood 87, Nr. 4 (15.02.1996): 1561–70. http://dx.doi.org/10.1182/blood.v87.4.1561.bloodjournal8741561.

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Myeloproliferative disorders and myelodysplastic syndromes arise in multipotent progenitors and may be associated with chromosomal deletions that can be detected in peripheral blood granulocytes. We present here seven patients with myeloproliferative disorders or myelodysplastic syndromes in whom a deletion of the long arm of chromosome 20 was detectable by G-banding and/or fluorescence in situ hybridization in most or all bone marrow metaphases. However, in each case, microsatellite polymerase chain reaction (PCR) using 15 primer pairs spanning the common deleted region on 20q showed that the deletion was absent from most peripheral blood granulocytes. The human androgen receptor clonality assay was used to show that the vast majority of peripheral blood granulocytes were clonal in all four female patients. This represents the first demonstration that the 20q deletion can arise as a second event in patients with pre-existing clonal granulopoiesis. Microsatellite PCR analysis of whole bone marrow from two patients was consistent with cytogenetic studies, a result that suggests that cytogenetic analysis was not merely selecting for a minor subclone of cells carrying the deletion. Furthermore, in one patient, the deletion was present in both erythroid and granulocyte/monocyte colonies. This implies that the absence of the deletion in most peripheral blood granulocytes did not reflect lineage restriction of the progenitors carrying the deletion but may instead result from other selective influences such as preferential retention/destruction within the bone marrow of granulocytes carrying the deletion.

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Lewis, Daniel J., und Madeleine Duvic. „A possible association between mycosis fungoides and Muir-Torre syndrome: Two disorders with microsatellite instability“. JAAD Case Reports 3, Nr. 4 (Juli 2017): 358–61. http://dx.doi.org/10.1016/j.jdcr.2017.04.007.

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Abidi, Asima, Mark A. J. Gorris, Evan Brennan, Marjolijn C. J. Jongmans, Dilys D. Weijers, Roland P. Kuiper, Richarda M. de Voer, Nicoline Hoogerbrugge, Gerty Schreibelt und I. Jolanda M. de Vries. „Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome“. Cancers 13, Nr. 10 (13.05.2021): 2345. http://dx.doi.org/10.3390/cancers13102345.

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Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.

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Giuffrida, Paolo, Alessandro Vanoli, Giovanni Arpa, Arturo Bonometti, Ombretta Luinetti, Enrico Solcia, Gino Corazza, Marco Paulli und Antonio Di Sabatino. „Small Bowel Carcinomas Associated with Immune-Mediated Intestinal Disorders: The Current Knowledge“. Cancers 11, Nr. 1 (29.12.2018): 31. http://dx.doi.org/10.3390/cancers11010031.

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Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders including coeliac disease (CD) and Crohn’s disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in tumour cell phenotype, frequency of microsatellite instability and nuclear β-catenin expression, as well as in prognosis. For these patients, high tumour-infiltrating lymphocyte density and glandular/medullary histotype represent independent positive prognostic factors. Dysplasia adjacent to SBC is rare and characterized by intestinal phenotype and nuclear β-catenin in CD, while it is frequent and typified by gastro-pancreatobiliary marker expression and preserved membranous β-catenin in CrD. Recent evidence suggests that Epstein-Barr virus-positive dysplasia and SBC, albeit exceptional, do exist and are associated with CrD. In this review, we summarize the novel pathological and molecular insights of clinical and therapeutic interest to guide the care of CD-SBC and CrD-SBC.

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Alonso-Navarro, Hortensia, Elena García-Martín, José A. G. Agúndez und Félix Javier Jiménez-Jiménez. „Association between restless legs syndrome and other movement disorders“. Neurology 92, Nr. 20 (19.04.2019): 948–64. http://dx.doi.org/10.1212/wnl.0000000000007500.

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ObjectiveThis review focuses on the possible association between restless legs syndrome (RLS) and movement disorders, including Parkinson disease (PD), other parkinsonian syndromes, essential tremor, choreic and dystonic syndromes, Tourette syndrome, and heredodegenerative ataxias.MethodsReview of PubMed from 1966 to September 2018 and identification of references of interest for the topic. A meta-analysis of eligible studies on the frequency of RLS in patients with PD and controls using Meta-DiSc1.1.1 software and using the PRISMA guidelines was performed.Results and conclusionsAlthough there are substantial clinical, neuroimaging, neuropathologic, and genetic differences between RLS and PD, many reports describe a higher than expected prevalence of RLS in patients with PD, when compared with the general population or with matched control groups; several studies have also suggested that RLS could be an early clinical feature of PD. RLS symptoms are frequent in multiple system atrophy, essential tremor, Tourette syndrome, Friedreich ataxia, and spinocerebellar ataxia type 3 as well. Finally, possible genetic links between PD and RLS (the presence of allele 2 of the complex microsatellite repeat Rep1 within the α-synuclein gene promoter) and between Tourette syndrome and RLS (several variants in theBTBD9gene) have been reported in 2 case–control association studies, although these data, based on preliminary data with small sample sizes, need to be replicated in further studies.

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Zhao, Xiaonan, und Karen Usdin. „(Dys)function Follows Form: Nucleic Acid Structure, Repeat Expansion, and Disease Pathology in FMR1 Disorders“. International Journal of Molecular Sciences 22, Nr. 17 (25.08.2021): 9167. http://dx.doi.org/10.3390/ijms22179167.

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Fragile X-related disorders (FXDs), also known as FMR1 disorders, are examples of repeat expansion diseases (REDs), clinical conditions that arise from an increase in the number of repeats in a disease-specific microsatellite. In the case of FXDs, the repeat unit is CGG/CCG and the repeat tract is located in the 5′ UTR of the X-linked FMR1 gene. Expansion can result in neurodegeneration, ovarian dysfunction, or intellectual disability depending on the number of repeats in the expanded allele. A growing body of evidence suggests that the mutational mechanisms responsible for many REDs share several common features. It is also increasingly apparent that in some of these diseases the pathologic consequences of expansion may arise in similar ways. It has long been known that many of the disease-associated repeats form unusual DNA and RNA structures. This review will focus on what is known about these structures, the proteins with which they interact, and how they may be related to the causative mutation and disease pathology in the FMR1 disorders.

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Nguyen, Lien, John Douglas Cleary und Laura P. W. Ranum. „Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease“. Annual Review of Neuroscience 42, Nr. 1 (08.07.2019): 227–47. http://dx.doi.org/10.1146/annurev-neuro-070918-050405.

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Microsatellite mutations involving the expansion of tri-, tetra-, penta-, or hexanucleotide repeats cause more than 40 different neurological disorders. Although, traditionally, the position of the repeat within or outside of an open reading frame has been used to focus research on disease mechanisms involving protein loss of function, protein gain of function, or RNA gain of function, the discoveries of bidirectional transcription and repeat-associated non-ATG (RAN) have blurred these distinctions. Here we review what is known about RAN proteins in disease, the mechanisms by which they are produced, and the novel therapeutic opportunities they provide.

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Potapov, Oleksii A., Anastasia Y. Glagolieva, Dmytro E. Makhmudov und Andrzej L. Komorowski. „Prognostic value of microsatellite instability in adjuvant treatment of colorectal cancer“. Postępy Higieny i Medycyny Doświadczalnej 72 (03.08.2018): 540–46. http://dx.doi.org/10.5604/01.3001.0012.1680.

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The dynamics of morbidity and mortality in colorectal cancer (CRC) has changed little in recent years and consistently remains at a high level. The carcinogenesis of this type of tumors includes a large number of genetic disorders and epigenetic changes, which show a number of features specific for this nosology, providing the basis for the first consensus classification of molecular subtypes for colorectal cancer. One of the main mechanisms chosen as crucial for this classification is the microsatellite instability (MSI) caused by defects in the DNA Mismatch Repair System (MMR). The clinical significance of this CRC molecular profile parameter is hard to overestimate. Over the past three decades, the MSI and MMR have been actively studied for prognosis evaluation, determination of need and selection of appropriate adjuvant chemotherapy scheme for CRC. Despite the significant accumulation of clinical and experimental study data, currently the prognostic value of this parameter is still not well defined with reference to CRC adjuvant treatment strategies, and the released data remain controversial. The purpose of this analytic review is to analyze the current status of MSI and MMR in the setting of adjuvant treatment of CRC patients from a perspective of evidence-based medicine.

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Maciocha, Filip, Aleksandra Suchanecka, Krzysztof Chmielowiec, Jolanta Chmielowiec, Andrzej Ciechanowicz und Agnieszka Boroń. „Correlations of the CNR1 Gene with Personality Traits in Women with Alcohol Use Disorder“. International Journal of Molecular Sciences 25, Nr. 10 (09.05.2024): 5174. http://dx.doi.org/10.3390/ijms25105174.

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Alcohol use disorder (AUD) is a significant issue affecting women, with severe consequences for society, the economy, and most importantly, health. Both personality and alcohol use disorders are phenotypically very complex, and elucidating their shared heritability is a challenge for medical genetics. Therefore, our study investigated the correlations between the microsatellite polymorphism (AAT)n of the Cannabinoid Receptor 1 (CNR1) gene and personality traits in women with AUD. The study group included 187 female subjects. Of these, 93 were diagnosed with alcohol use disorder, and 94 were controls. Repeat length polymorphism of microsatellite regions (AAT)n in the CNR1 gene was identified with PCR. All participants were assessed with the Mini-International Neuropsychiatric Interview and completed the NEO Five-Factor and State-Trait Anxiety Inventories. In the group of AUD subjects, significantly fewer (AAT)n repeats were present when compared with controls (p = 0.0380). While comparing the alcohol use disorder subjects (AUD) and the controls, we observed significantly higher scores on the STAI trait (p < 0.00001) and state scales (p = 0.0001) and on the NEO Five-Factor Inventory Neuroticism (p < 0.00001) and Openness (p = 0.0237; insignificant after Bonferroni correction) scales. Significantly lower results were obtained on the NEO-FFI Extraversion (p = 0.00003), Agreeability (p < 0.00001) and Conscientiousness (p < 0.00001) scales by the AUD subjects when compared to controls. There was no statistically significant Pearson’s linear correlation between the number of (AAT)n repeats in the CNR1 gene and the STAI and NEO Five-Factor Inventory scores in the group of AUD subjects. In contrast, Pearson’s linear correlation analysis in controls showed a positive correlation between the number of the (AAT)n repeats and the STAI state scale (r = 0.184; p = 0.011; insignificant after Bonferroni correction) and a negative correlation with the NEO-FFI Openness scale (r = −0.241; p = 0.001). Interestingly, our study provided data on two separate complex issues, i.e., (1) the association of (AAT)n CNR1 repeats with the AUD in females; (2) the correlation of (AAT)n CNR1 repeats with anxiety as a state and Openness in non-alcohol dependent subjects. In conclusion, our study provided a plethora of valuable data for improving our understanding of alcohol use disorder and anxiety.

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Freund, Aline Andrade, Rosana Hermínia Scola, Hélio A. G. Teive, Raquel Cristina Arndt, Magda Clara Vieira da Costa-Ribeiro, Lupe Furtado Alle und Lineu Cesar Werneck. „Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals“. Arquivos de Neuro-Psiquiatria 67, Nr. 4 (Dezember 2009): 1124–32. http://dx.doi.org/10.1590/s0004-282x2009000600034.

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The diagnosis and incidence of spinocerebelar ataxias (SCA) is sometimes difficult to analyze due the overlap of phenotypes subtypes and are disorders of mutations caused by CAG trinucleotide repeat expansion. To investigate the incidence of the SCA in Southern Brazil, we analyzed the trinucleotide repeats (CAG)n at the SCA1, SCA2, SCA3, SCA6 and SCA7 loci to identify allele size ranges and frequencies. We examined blood sample from 154 asymptomatic blood donors and 115 individuals with progressive ataxias. PCR products were submitted to capillary electrophoresis. In the blood donors, the ranges of the five loci were: SCA1, 19 to 36 (CAG)n; SCA2, 6 to 28 (CAG)n; SCA3, 12 to 34 (CAG)n; SCA6, 2 to 13 (CAG)n; and SCA7, 2 to 10 (CAG)n. No deviations from Hardy-Weinberg equilibrium were detected. In the ataxia group, we found (CAG)n above the range of the asymptomatic blood donors in SCA3 (21.74%) followed by SCA2 (5.22%), SCA7 (2.61%), SCA6 (0.87%), and no cases of SCA1. The remaining 80 cases (69.56%) have different diagnoses from the type here studied. These data defined the alleles and their frequencies, as well as demonstrated their stability in the population not affected. The molecular diagnosis test confirmed the clinical diagnosis in 28/45 cases and classified another 7/70 from the clinical unclassified ataxias group.

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Franchina, M. „Polymorphism of the CD30 Promoter Microsatellite Repressive Element Is Associated with Development of Primary Cutaneous Lymphoproliferative Disorders“. Cancer Epidemiology Biomarkers & Prevention 14, Nr. 5 (01.05.2005): 1322–25. http://dx.doi.org/10.1158/1055-9965.epi-04-0826.

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De Molfetta, Greice Andreotti, Temis Maria Felix, Mariluce Riegel, Victor Evangelista de Faria Ferraz und João Monteiro de Pina Neto. „A further case of a Prader-Willi syndrome phenotype in a patient with Angelman syndrome molecular defect“. Arquivos de Neuro-Psiquiatria 60, Nr. 4 (Dezember 2002): 1011–14. http://dx.doi.org/10.1590/s0004-282x2002000600024.

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Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct human neurogenetic disorders; however, a clinical overlap between AS and PWS has been identified. We report on a further case of a patient showing the PWS phenotype with the AS molecular defect. Despite the PWS phenotype, the DNA methylation analysis of SNRPN revealed an AS pattern. Cytogenetic and FISH analysis showed normal chromosomes 15 and microsatellite analysis showed heterozygous loci inside and outside the 15q11-13 region. The presence of these atypical cases could be more frequent than previously expected and we reinforce that the DNA methylation analysis is important for the correct diagnosis of severe mental deficiency, congenital hypotonia and obesity.

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Theocharides, Alexandre, Marjorie Boissinot, François Girodon, Richard Garand, Soon-Siong Teo, Eric Lippert, Pascaline Talmant, Andre Tichelli, Sylvie Hermouet und Radek C. Skoda. „Leukemic blasts in transformed JAK2-V617F–positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation.“ Blood 110, Nr. 1 (01.07.2007): 375–79. http://dx.doi.org/10.1182/blood-2006-12-062125.

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To study the role of the JAK2-V617F mutation in leukemic transformation, we examined 27 patients with myeloproliferative disorders (MPDs) who transformed to acute myeloid leukemia (AML). At MPD diagnosis, JAK2-V617F was detectable in 17 of 27 patients. Surprisingly, only 5 of 17 patients developed JAK2-V617F–positive AML, whereas 9 of 17 patients transformed to JAK2-V617F–negative AML. Microsatellite analysis in a female patient showed that mitotic recombination was not responsible for the transition from JAK2-V617F–positive MPD to JAK2-V617F–negative AML, and clonality determined by the MPP1 polymorphism demonstrated that the granulocytes and leukemic blasts inactivated the same parental X chromosome. In a second patient positive for JAK2-V617F at transformation, but with JAK2-V617F–negative leukemic blasts, we found del(11q) in all cells examined, suggesting a common clonal origin of MPD and AML. We conclude that JAK2-V617F–positive MPD frequently yields JAK2-V617F–negative AML, and transformation of a common JAK2-V617F–negative ancestor represents a possible mechanism.

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Galbraith, G. M. P. „Polymorphism of the CD30 Promoter Microsatellite Repressive Element Is Associated With Development of Primary Cutaneous Lymphoprolifer-ative Disorders“. Yearbook of Dermatology and Dermatologic Surgery 2006 (Januar 2006): 369–70. http://dx.doi.org/10.1016/s0093-3619(08)70305-8.

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Peddareddygari, Leema Reddy, Phillip D. Kramer, Philip A. Hanna, Mark A. Levenstien und Raji P. Grewal. „Genetic Analysis of a Large Family with Migraine, Vertigo, and Motion Sickness“. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 46, Nr. 5 (01.07.2019): 512–17. http://dx.doi.org/10.1017/cjn.2019.64.

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ABSTRACT:Background: Migraine is a common disorder most typically presenting as headache and often associated with vertigo and motion sickness. It is a genetically complex condition with multiple genes ultimately contributing to the predisposition and development of this episodic neurological disorder. We identified a large American family of 29 individuals of which 17 members suffered from at least one of these disorders, migraine, vertigo, or motion sickness. Many of these individuals suffered from several simultaneously. We hypothesized that vertigo and motion sickness may involve genes that are independent to those directly contributing to migraine susceptibility. Methods: Genome-wide linkage analysis performed using 400 microsatellite repeat markers spaced at 10 cM throughout the genome. The members of this family were phenotyped for each condition, migraine, vertigo, and motion sickness and analyzed separately. Statistical analysis was performed using two-point and multipoint linkage analysis employing a number of models including autosomal recessive or dominant patterns of inheritance with high and low genetic penetrance. Results: We identified a novel locus for migraine, 9q13-q22 (maximum two-point logarithm of odds [LOD] score-2.51). In addition, there are suggestive LOD scores that localize to different chromosomes for each phenotype; vertigo (chromosome 18, LOD score of 1.82) and motion sickness (chromosome 4, LOD score of 2.09). Conclusions: Our analysis supports our hypothesis that the migraine-associated vertigo and motion sickness may involve distinct susceptibility genes.

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KRZEMIŃSKA, PAULINA, MACIEJ GOGULSKI, ROMAN ALEKSIEWICZ und MAREK ŚWITOŃSKI. „Genetic markers of canine hip dysplasia“. Medycyna Weterynaryjna 74, Nr. 2 (2018): 6069–2018. http://dx.doi.org/10.21521/mw.6069.

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Canine hip dysplasia is a complex skeletal malformation caused by genetic and environmental factors. The prevalence of hip dysplasia in different canine breeds ranges widely, from 1% (for Whippet and Borzoi) to over 70% (for Bulldog and Pug). These differences indicate the presence of genetic variants predisposing to or preventing this disorder in gene pools of particular breeds. The importance of genetic factors is also confirmed by a high coefficient of heritability (h2) of canine hip dysplasia, which for most breeds oscillates around 0.5 – 0.6. Application of modern genomic methods, that is, mainly genome scanning (based previously on microsatellite markers and currently on SNP microarrays) has led in recent years to the identification of potential genetic markers associated with this disorder. Such studies were carried out mostly in two breeds: Labrador retriever and German shepherd. Some of the markers were found in the vicinity of genes involved in skeletal development. Following these achievements, the use of some markers has been suggested for early risk diagnosis of hip dysplasia. This shows that molecular testing is becoming important for not only monogenic, but also polygenic canine diseases and disorders. Identification of genetic markers associated with predisposition to hip dysplasia offers an opportunity for an early risk evaluation of this disorder (prior to its first signs). Moreover, it facilitates effective breeding selection aimed at eradicating undesirable genetic variants from the gene pool of a given breed..

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White, NJ, E. Nacheva, FA Asimakopoulos, D. Bloxham, B. Paul und AR Green. „Deletion of chromosome 20q in myelodysplasia can occur in a multipotent precursor of both myeloid cells and B cells“. Blood 83, Nr. 10 (15.05.1994): 2809–16. http://dx.doi.org/10.1182/blood.v83.10.2809.2809.

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Abstract Deletions of the long arm of chromosome 20 are associated with several myeloid malignancies and, in particular, with myeloproliferative disorders and myelodysplastic syndromes (MDS). Together with deletions of chromosome 5q and chromosome 7q, chromosome 20q deletions have previously been thought to be restricted to myeloid cells in patients with MDS. We report here that deletion of chromosome 20q in MDS can arise in a multipotent precursor of both myeloid cells and B cells. Clonal Epstein-Barr virus (EBV)-transformed cell lines, both with and without a 20q deletion, have been isolated from a patient with MDS. Moreover, these cell lines have been shown to provide a useful physical mapping tool and have been used to confirm the interstitial nature of the 20q deletion. Microsatellite polymerase chain reaction (PCR) and PCR analysis of PGK gene methylation have been used to study highly purified populations of peripheral blood cells. The 20q deletion was detectable by microsatellite PCR in peripheral blood granulocytes and monocytes but not in B cells or T cells. Clonality of the different lineages followed the same pattern as the 20q deletion. This represents the first report in which a chromosome abnormality associated with MDS has been immortalized in an EBV-transformed lymphoblastoid cell line. Furthermore, our data show that patients with apparent myeloid restriction of a chromosome deletion may in fact have a disease arising in a multipotent cell with both myeloid and lymphoid potential.

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Yoo, Hanik K., Seockhoon Chung, Jin Pyo Hong, Boong-Nyun Kim und Soo Churl Cho. „Microsatellite Marker in Gamma - Aminobutyric Acid - A Receptor Beta 3 Subunit Gene and Autism Spectrum Disorders in Korean Trios“. Yonsei Medical Journal 50, Nr. 2 (2009): 304. http://dx.doi.org/10.3349/ymj.2009.50.2.304.

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Asimakopoulos, FA, NJ White, E. Nacheva und AR Green. „Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes“. Blood 84, Nr. 9 (01.11.1994): 3086–94. http://dx.doi.org/10.1182/blood.v84.9.3086.3086.

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Abstract Acquired deletions of the long arm of chromosome 20 are found in several hematologic conditions and particularly in the myeloproliferative disorders and myelodysplastic syndromes. The spectrum of diseases associated with 20q deletions suggests that such deletions may mark the site of a tumor suppressor gene that contributes to the regulation of normal multipotent hematopoietic progenitors. We present here the first detailed molecular analysis of 20q deletions associated with myeloid disorders. Thirty-four microsatellite primer pairs corresponding to loci on 20q have been used to study DNA samples from two cell lines and from highly purified peripheral blood granulocytes obtained from seven patients. In addition, Southern analysis of cell line DNA has been performed using 19 DNA probes that map to 20q. Three conclusions can be drawn from our results. Firstly, molecular heterogeneity of both centromeric and telomeric breakpoints was demonstrated, thus supporting the existence of a tumor suppressor gene on 20q. In addition many of the breakpoints have been mapped to small genetic intervals. Secondly, our results define a commonly deleted region of 16–21 cM which contains ADA, PLC1, TOP1, SEMG1, and PPGB. Several candidate tumor suppressor genes lie outside the common deleted region including SRC, HCK, p107, PTPN1, and CEBP beta. Thirdly, the data allow integration of genetic and physical maps and have refined the map positions of multiple genes. These results will facilitate attempts to identify candidate hematopoietic tumor suppressor genes on 20q.

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Asimakopoulos, FA, NJ White, E. Nacheva und AR Green. „Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes“. Blood 84, Nr. 9 (01.11.1994): 3086–94. http://dx.doi.org/10.1182/blood.v84.9.3086.bloodjournal8493086.

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Acquired deletions of the long arm of chromosome 20 are found in several hematologic conditions and particularly in the myeloproliferative disorders and myelodysplastic syndromes. The spectrum of diseases associated with 20q deletions suggests that such deletions may mark the site of a tumor suppressor gene that contributes to the regulation of normal multipotent hematopoietic progenitors. We present here the first detailed molecular analysis of 20q deletions associated with myeloid disorders. Thirty-four microsatellite primer pairs corresponding to loci on 20q have been used to study DNA samples from two cell lines and from highly purified peripheral blood granulocytes obtained from seven patients. In addition, Southern analysis of cell line DNA has been performed using 19 DNA probes that map to 20q. Three conclusions can be drawn from our results. Firstly, molecular heterogeneity of both centromeric and telomeric breakpoints was demonstrated, thus supporting the existence of a tumor suppressor gene on 20q. In addition many of the breakpoints have been mapped to small genetic intervals. Secondly, our results define a commonly deleted region of 16–21 cM which contains ADA, PLC1, TOP1, SEMG1, and PPGB. Several candidate tumor suppressor genes lie outside the common deleted region including SRC, HCK, p107, PTPN1, and CEBP beta. Thirdly, the data allow integration of genetic and physical maps and have refined the map positions of multiple genes. These results will facilitate attempts to identify candidate hematopoietic tumor suppressor genes on 20q.

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Lee, Johanna E., und Thomas A. Cooper. „Pathogenic mechanisms of myotonic dystrophy“. Biochemical Society Transactions 37, Nr. 6 (19.11.2009): 1281–86. http://dx.doi.org/10.1042/bst0371281.

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DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3′-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)n or (CCUG)n. The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.

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Sychevskaya, Kseniia Andreevna, N. V. Risinskaya, S. K. Kravchenko, E. E. Nikulina, A. E. Misyurina, A. U. Magomedova und A. B. Sudarikov. „Pitfalls in mononucleotide microsatellite repeats instability assessing (MSI) in the patients with B-cell lymphomas“. Russian Clinical Laboratory Diagnostics 66, Nr. 3 (30.03.2021): 181–86. http://dx.doi.org/10.51620/0869-2084-2021-66-3-181-186.

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Analysis of microsatellite instability (MSI) is a routine study in the diagnostics of solid malignancies. The standard for determining MSI is a pentaplex PCR panel of mononucleotide repeats: NR-21, NR-24, NR-27, BAT-25, BAT-26. The presence of MSI is established based on differences in the length of markers in the tumor tissue and in the control, but due to the quasimonomorphic nature of standard mononucleotide loci the use of a control sample is not necessary in the diagnosis of MSI-positive solid tumors. The significance of the MSI phenomenon in oncohematology has not been established. This paper presents the results of a study of MSI in B-cell lymphomas: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL). We have shown that aberrations of mononucleotide markers occur in these diseases, but the nature of the changes does not correspond to the classical MSI in solid neoplasms. This fact requires further study of the pathogenesis of such genetic disorders. Due to the possibility of ambiguous interpretation of the results of the MSI study for previously uncharacterized diseases, strict compliance with the methodology of parallel analysis of the tumor tissue and the control sample is mandatory.

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Choufani, Sanaa, Jung Min Ko, Youliang Lou, Cheryl Shuman, Leona Fishman und Rosanna Weksberg. „Paternal Uniparental Disomy of the Entire Chromosome 20 in a Child with Beckwith-Wiedemann Syndrome“. Genes 12, Nr. 2 (27.01.2021): 172. http://dx.doi.org/10.3390/genes12020172.

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Epigenetic alterations at imprinted genes on different chromosomes have been linked to several imprinting disorders (IDs) such as Beckwith-Wiedemann syndrome (BWS) and pseudohypoparathyroidism type 1b (PHP1b). Here, we present a male patient with these two distinct IDs caused by two independent mechanisms-loss of methylation (LOM) at chromosome 11p15.5 associated with multi-locus imprinting disturbances (MLID and paternal uniparental disomy of chromosome 20 (patUPD20). A clinical diagnosis of BWS was made based on the clinical features of macrosomia, macroglossia, and umbilical hernia. The diagnosis of PHP1b was supported by the presence of reduced growth velocity and mild learning disability as well as hypocalcemia and hyperphosphatemia at 14 years of age. Molecular analyses, including genome-wide DNA methylation (Illumina 450k array), bisulfite pyrosequencing, single nucleotide polymorphism (SNP) array and microsatellite analysis, demonstrated loss of methylation (LOM) at IC2 on chromosome 11p15.5, and paternal isodisomy of the entire chromosome 20. In addition, imprinting disturbances were noted at the differentially methylated regions (DMRs) associated with DIRAS3 on chromosome 1 and PLAGL1 on chromosome 6. This is the first case report of PHP1b due to patUPD20 diagnosed in a BWS patient with LOM at IC2 demonstrating etiologic heterogeneity for multiple imprinting disorders in a single individual.

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Schaub, Franz X., Roland Jäger, Renate Looser, Hui Hao-Shen, Sylvie Hermouet, François Girodon, Andre Tichelli, Heinz Gisslinger, Robert Kralovics und Radek C. Skoda. „Clonal analysis of deletions on chromosome 20q and JAK2-V617F in MPD suggests that del20q acts independently and is not one of the predisposing mutations for JAK2-V617F“. Blood 113, Nr. 9 (26.02.2009): 2022–27. http://dx.doi.org/10.1182/blood-2008-07-167056.

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We developed a real-time copy number polymerase chain reaction assay for deletions on chromosome 20q (del20q), screened peripheral blood granulocytes from 664 patients with myeloproliferative disorders, and identified 19 patients with del20q (2.9%), of which 14 (74%) were also positive for JAK2-V617F. To examine the temporal relationship between the occurrence of del20q and JAK2-V617F, we performed colony assays in methylcellulose, picked individual burst-forming units–erythroid (BFU-E) and colony-forming units–granulocyte (CFU-G) colonies, and genotyped each colony individually for del20q and JAK2-V617F. In 2 of 9 patients, we found that some colonies with del20q carried only wild-type JAK2, whereas other del20q colonies were JAK2-V617F positive, indicating that del20q occurred before the acquisition of JAK2-V617F. However, in colonies from 3 of 9 patients, we observed the opposite order of events. The lack of a strict temporal order of occurrence makes it doubtful that del20q represents a predisposing event for JAK2-V617F. In 2 patients with JAK2-V617F and 1 patient with MPL-W515L, microsatellite analysis revealed that del20q affected chromosomes of different parental origin and/or 9pLOH occurred at least twice. The fact that rare somatic events, such as del20q or 9pLOH, occurred more than once in subclones from the same patients suggests that the myeloproliferative disorder clone carries a predisposition to acquiring such genetic alterations.

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Castoldi, Elisabetta, Barbara Lunghi, Federico Mingozzi, Paolo Simioni, Antonio Girolami und Francesco Bernardi. „A highly polymorphic microsatellite in the factor V gene is an informative tool for the study of factor V-related disorders“. British Journal of Haematology 114, Nr. 4 (September 2001): 868–70. http://dx.doi.org/10.1046/j.1365-2141.2001.03052.x.

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T, Muthu Venkat, Vijayalakshmi Vijayalakshmi und Pramila Pramila. „Significance of Microsatellite Instability in Colorectal Carcinoma- A Complete Review“. Saudi Journal of Pathology and Microbiology 9, Nr. 03 (27.03.2024): 71–74. http://dx.doi.org/10.36348/sjpm.2024.v09i03.003.

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The microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) colorectal tumors recently have been reported that can benefit from immunotherapy, and MSI can be used as a genetic instability of a tumor detection index. Many studies have shown that there are many heterogeneous phenomena in patients with MSI tumors in terms of immunotherapy, prognosis and chemotherapy sensitivity. Here we mainly review the research results of MSI detection methods, its mechanisms, occurrence and its relationship with related tumors, aiming in such a way for brief analysis of the micro satellite instability. Microsatellites (MS) are the repeated sequences of DNA that play an important role in maintaining the tissue morphology. Any mutation of the DNA or chromosomes, lead to the instability of the microsatellites, thereby causing the microsatellite instability. There are three types of microsatellite instability (MSI). High microsatellite instability (MSI-H), low microsatellite instability (MSI-L) and microsatellite stability (MSS). Recent clinical research tends to classify MSS-L and MSS as similar. Microstaellite instability plays an important role in colorectal carcinoma. Based on different molecular mechanisms, MSI in colorectal cancer can be divided into colorectal cancer (CRC) with no obvious family genetic history and Lynch syndrome with non-polyposis with family genetic history. Lynch syndrome is an autosomal dominant disorder and syndrome caused by mutations in MMR strains, and it can also cause tumors in other parts of the colon and rectum. With the recent development of MSI detection technology and immunosuppressant in tumor therapy, researchers found that MSI-H tumors respond well to immunotherapy. There are several methods to detect the microsatellite instability. 1. Next Generation sequencing (NGS), 2. Fluoresence multiplex PCR and capillary electrophoresis. 3. Immunohistochemistry. 4. Single molecule- molecular inversion probes (SmMIP). The main mechanism of MSI includes, Slipped strand mispairing, MMR deficient.

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Peral, Belén, José L. San Millán, Roberto Castello, Paolo Moghetti und Héctor F. Escobar-Morreale. „The Methionine 196 Arginine Polymorphism in Exon 6 of the TNF Receptor 2 Gene (TNFRSF1B) Is Associated with the Polycystic Ovary Syndrome and Hyperandrogenism“. Journal of Clinical Endocrinology & Metabolism 87, Nr. 8 (01.08.2002): 3977–83. http://dx.doi.org/10.1210/jcem.87.8.8715.

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Inflammatory cytokines such as TNFα may play a role in the pathogenesis of common metabolic disorders, including hyperandrogenism and the polycystic ovary syndrome (PCOS). The TNF receptor 2 mediates most of the metabolic effects of TNFα. In the present study, we have evaluated serum soluble TNF receptor 2 levels, and several common polymorphisms in the TNF receptor 2 gene (TNFRSF1B), in women presenting with PCOS or hyperandrogenic disorders. Initial studies included 103 hyperandrogenic patients (42 presenting with PCOS) and 36 controls from Spain. The 196R alleles of the M196R (676 T→G) variant in exon 6 of TNFRSF1B, which is in linkage disequilibrium with a CA-repeat microsatellite polymorphism in intron 4 of TNFRSF1B, tended to be more frequent in hyperandrogenic patients than in controls (P = 0.056), reaching statistical significance when the analysis was restricted to include only PCOS patients (P < 0.03). Extended analysis including another 11 hyperandrogenic patients from Spain and 64 patients and 29 controls from Italy confirmed the association between 196R alleles of the M196R variant and hyperandrogenic disorders (P < 0.05), which was maintained when restricting the analysis to PCOS patients (P < 0.02). On the contrary, the 3′-untranslated region (exon 10) variants 1663 G→A, 1668 T→G, and 1690 T→C were not associated with hyperandrogenism. The soluble TNF receptor 2 levels were not different between patients and controls but were increased in obese subjects, compared with lean individuals, and were affected by the interaction between the 1663 G→A and 1668 T→G variants in the 3′-untranslated region of TNFRSF1B. The TNFRSF1B genotype did not influence any clinical or biochemical variable related to hyperandrogenism or insulin sensitivity and was not associated with obesity, both in hyperandrogenic patients and healthy controls considered separately. In conclusion, the M196R (676 T→G) variant in exon 6 of TNFRSF1B is associated with hyperandrogenism and PCOS, further suggesting a role for inflammatory cytokines in the pathogenesis of these disorders.

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Weinhaeusel, Andreas, Susanne Thiele, Manuela Hofner, Olaf Hiort und Christa Noehammer. „PCR-Based Analysis of Differentially Methylated Regions of GNAS Enables Convenient Diagnostic Testing of Pseudohypoparathyroidism Type Ib“. Clinical Chemistry 54, Nr. 9 (01.09.2008): 1537–45. http://dx.doi.org/10.1373/clinchem.2008.104216.

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Abstract Background: Pseudohypoparathyroidism type Ib (PHPIb) is characterized by parathyroid hormone (PTH) resistance, which can lead to hypocalcemia, hyperphosphatemia, and increased serum PTH. The disorder is caused by mutations in regulatory regions of the GNAS gene (GNAS complex locus) that lead to interferences in the methylation status of alternative GNAS promoters, such as exon A/B, NESP55, and XLα-s. PHPIb comprises disorders that show distinctive changes in methylation status but share the same clinical phenotype: (a) loss of methylation only at exon A/B of the GNAS gene and involving no other obvious epigenetic abnormalities [e.g., those caused by heterozygous microdeletions in the STX16 (syntaxin 16) region and found in many patients with autosomal dominant (AD) PHPIb]; (b) methylation abnormalities at several differentially methylated regions (DMRs), which are observed in most patients with sporadic PHPIb and some families with AD PHPIb. Methods: To permit early and reliable diagnosis of suspected PHPIb, we designed methylation-sensitive restriction enzyme–based and bisulfite deamination–based PCR tests for exon A/B and NESP55 DMRs. Results: Both PCR strategies permit proper methylation testing of GNAS and NESP55 DMRs and elucidate different disease subtypes. We have identified a novel microsatellite repeat polymorphism within GNAS exon A/B, and pedigree analyses have shown its presence to be conclusive evidence for familial disease. Conclusions: We provide a simple diagnostic test for PHPIb, an imprinting disorder caused by different molecular changes within the GNAS complex locus. PHPIb, a complex and diagnostically challenging clinical phenotype, can be treated successfully by taking steps before the manifestation of symptoms to avoid clinical complications in affected patients or asymptomatic members of affected families who show positive results in genetic tests.

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Bekki, Tomoaki, Yuji Takakura, Masatoshi Kochi, Yoko Konemori, Kenji Oki, Masayasu Yoneda, Hiroyuki Egi und Hideki Ohdan. „A Case of Isolated Adrenocorticotropic Hormone Deficiency Caused by Pembrolizumab“. Case Reports in Oncology 13, Nr. 1 (05.03.2020): 200–206. http://dx.doi.org/10.1159/000505687.

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Pembrolizumab (Keytruda®) is an anti-programmed cell death 1-specific monoclonal antibody that has become the standard second-line chemotherapy for unresectable advanced microsatellite instability-high colorectal cancer. Several immune-related adverse events (irAEs), particularly endocrinopathy, are linked to the administration of pembrolizumab. We report here a case of pembrolizumab-induced isolated adrenocorticotropic hormone deficiency in a patient with metastatic colon cancer. A 65-year-old woman visited our hospital for complaints of fatigue with a recent history of primary resection of cecal mucinous cancer and hepatectomy for liver metastasis 3 years ago. Peritoneal dissemination was detected 2 years after surgery. Several chemotherapeutic regimens of cytotoxic and molecular targeted drugs were administered; however, the metastases progressed gradually. Pembrolizumab monotherapy was started because of resistance to treatment. After 2 cycles of pembrolizumab, the patient was severely fatigued. Laboratory data demonstrated that the cortisol level was extremely low. All the other values were within the normal range. Magnetic resonance imaging indicated no mass in the pituitary gland. From multiple tolerance tests, we diagnosed isolated adrenocorticotropic hormone deficiency caused by pembrolizumab. The patient’s symptoms improved promptly with cortisol treatment. An abdominal contrast-enhanced computed tomography scan after 5 cycles of pembrolizumab demonstrated that the size of the peritoneal dissemination remained unchanged. However, her serum level of carcinoembryonic antigen had decreased to normal levels. Endocrine disorders are very rarely seen as irAEs. Careful laboratory data follow-up is required to inhibit the progression of severe endocrine disorders.

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Kenyon, Jonathan D., Youngji Park, Randall E. Marcus, Victor M. Goldberg und Stanton L. Gerson. „Human Hematopoietic Progenitor Cells Exhibit Increased Microsatellite Instability Associated with Advanced Age.“ Blood 106, Nr. 11 (16.11.2005): 2284. http://dx.doi.org/10.1182/blood.v106.11.2284.2284.

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Abstract The etiology of the aging process in human hematopoietic progenitor cells (HPCs) and how this relates to diseases associated with aging, such as leukemia myelodysplasia, anemia, bone marrow failure, and altered immune function, remains unclear. We hypothesize that DNA mismatch repair (MMR) defects, specifically in HPCs, might contribute to genomic instability and in turn hematopoietic diseases of the elderly. An increase in microsatellite instability (MSI), a characteristic of MMR defects, has been shown in the peripheral blood (Neri, et al. J. Gerontol., 2005) as well as in T-cells of healthy individuals (Kirchevsky, et al. Exp. Gerontol., 2004) as a function of age but has not been examined in clonal hematopoiesis of normal individuals. Mice who receive bone marrow transplants from MMR deficient mice show increased incidence of MSI, as well as mortality due to bone marrow stem cell failure (Reese, et al. Blood, 2003). Loss of MMR pathway components have also been reported in non-polyposis colorectal cancer, myelomas, and T-cell leukemia. To study MMR deficiency in HPCs during the normal aging process, we have tested DNA of 24 CFU grown in human methylcellulose from the mononuclear fraction of three human umbilical cord blood samples (at birth), 3 human bone marrow aspirates ages 18–49 yr (middle age), and 3 human bone core samples ages 50–85 yr (older) from total hip or knee replacement patients. Each CFU was tested for MSI at five loci (BAT25, BAT26, D2S123, D5S346, and D17S250) and given a ranking: stable (MSS), no MSI at any of the 5 loci; low frequency MSI (MSI-L), MSI seen at only one locus; or high frequency MSI (MSI-H) MSI seen at two or more loci. All five of the MSI loci were informative in at least one sample. 5′ fluorescently labeled forward primers for the MSI loci were used with unlabeled reverse primers to amplify DNA prepared from CFU. These fragments were analyzed by denaturing polyacrylamide gel and Typhoon 9200 phosphoimager. A positive MSI was scored for a CFU at a particular locus if significant differences were seen between the fragment lengths of other CFU from the same patient sample at the same locus. The average frequency of MSS CFU for the, “at birth” samples was: 69% ± 40%; for the, “middle age” samples: 47% ± 6%; for the, “older” samples: 54% ± 17%. The average frequency of MSI-L CFU for the “at birth” samples was: 28% ± 34%; for the, “middle age” samples: 51% ± 6%; for the, “older” samples: 40% ± 10%. Finally, the average frequency of MSI-H CFU for the “at birth” samples was 1% ± 2%; for the “middle age” samples was 1% ± 2%; for the “older” samples was 13% ± 8%. Our preliminary results show a nearly ten fold increase in frequency of MSI-H CFU seen in the older donors over younger age donors. This suggests that there may be a dramatic decline in MMR function associated with advanced age. This is the first data showing MMR deficiency associated with age in clones derived from normal human hematopoietic progenitor cells. If confirmed MMR may be an important target for both risk assessment and intervention to prevent marrow associated disorders.

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Gómez, Rocío, Yessica S. Tapia-Guerrero, Bulmaro Cisneros, Lorena Orozco, César Cerecedo-Zapata, Elvia Mendoza-Caamal, Gerardo Leyva-Gómez, Norberto Leyva-García, Luis Velázquez-Pérez und Jonathan J. Magaña. „Genetic Distribution of Five Spinocerebellar Ataxia Microsatellite Loci in Mexican Native American Populations and Its Impact on Contemporary Mestizo Populations“. Genes 13, Nr. 1 (16.01.2022): 157. http://dx.doi.org/10.3390/genes13010157.

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Spinocerebellar ataxias (SCAs) conform a heterogeneous group of neurodegenerative disorders with autosomal dominant inheritance. Five of the most frequent SCAs are caused by a CAG repeat expansion in the exons of specific genes. The SCAs incidence and the distribution of polymorphic CAG alleles vary among populations and ethnicities. Thus, characterization of the genetic architecture of ethnically diverse populations, which have undergone recent admixture and demographic events, could facilitate the identification of genetic risk factors. Owing to the great ethnic diversity of the Mexican population, this study aimed to analyze the allele frequencies of five SCA microsatellite loci (SCA1, SCA2, SCA3, SCA6, and SCA7) in eleven Mexican Native American (MNA) populations. Data from the literature were used to compare the allelic distribution of SCA loci with worldwide populations. The SCA loci allelic frequencies evidenced a certain genetic homogeneity in the MNA populations, except for Mayans, who exhibited distinctive genetic profiles. Neither pathological nor large normal alleles were found in MNA populations, except for the SCA2 pre-mutated allele in the Zapotec population. Collectively, our findings demonstrated the contribution of the MNA ancestry in shaping the genetic structure of contemporary Mexican Mestizo populations. Our results also suggest that Native American ancestry has no impact on the origin of SCAs in the Mexican population. Instead, the acquisition of pathological SCA alleles could be associated with European migration.

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Rodina, A. D., V. G. Polyakov, A. S. Krylov, V. V. Semenova, V. M. Kozlova, T. V. Nasedkina, A. L. Kashanina, N. A. Kozlov, V. V. Migunova und T. V. Gorbunova. „CMMRD-associated embryonic rhabdomyosarcoma in a child. Clinical case with literature review“. Russian Journal of Pediatric Hematology and Oncology 10, Nr. 3 (30.11.2023): 89–100. http://dx.doi.org/10.21682/2311-1267-2023-10-3-89-100.

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Introduction. Hereditary disorders in the DNA repair system can lead to the development of malignant neoplasms in childhood. DNA constitutional mismatch repair deficiency syndrome (CMMRD) is a very rare genetic autosomal recessive disorder caused by homozygous mutations in one of the four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The frequency of occurrence is 0.0000001 of the adult and child population. For now about 150 observations have been published in the world literature. The prognosis for CMMRD syndrome is extremely unfavorable. The spectrum of tumors that make up the CMMRD syndrome is very wide, and includes mainly malignant brain tumors, tumors of the digestive tract, hematological malignancies, embryonic tumors, all of which develop in childhood.The purpose of the study is to report a case of CMMRD-associated embryonic rhabdomyosarcoma in a 3-year-old child.Conclusions. A review of the literature and the clinical case we have described show that rhabdomyosarcoma belongs to the tumor spectrum of the CMMRD syndrome. An immunohistochemical study revealed an isolated loss of PMS2 gene expression. Taking into account the clinical course of the CMMRD syndrome, a thorough study of the family history in patients with rhabdomyosarcoma is recommended, as well as a molecular genetic study, including the search for germinal mutations in genes in the DNA repair system and the assessment of microsatellite instability in the material of the tumor tissue. The clinical symptoms of CMMRD syndrome are nonspecific and depend on the morphological variant of the primary tumor. Distinctive molecular genetic features of this syndrome are: homozygous mutations with loss of function of the germline genes of the MMR system (mismatch repair) (MLH1, MSH2, MSH6 or PMS2).

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