Статті в журналах: "R274W"

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Dang, Xiawei, Emily K. Walton, Barbara Zablocka, Robert H. Baloh, Michael E. Shy, and Gerald W. Dorn. "Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation." Cells 11, no. 6 (March 21, 2022): 1053. http://dx.doi.org/10.3390/cells11061053.

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Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot–Marie–Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson’s and Alzheimer’s disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.

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Jennings, Juliet E., Marianthi Georgitsi, Ian Holdaway, Adrian F. Daly, Maria Tichomirowa, Albert Beckers, Lauri A. Aaltonen, Auli Karhu, and Fergus J. Cameron. "Aggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene." European Journal of Endocrinology 161, no. 5 (November 2009): 799–804. http://dx.doi.org/10.1530/eje-09-0406.

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ObjectiveMutations in the aryl hydrocarbon receptor-interacting protein (AIP) were recently shown to confer a pituitary adenoma predisposition in patients with familial isolated pituitary adenomas (FIPA). We report a large Samoan FIPA kindred from Australia/New Zealand with an R271W mutation that was associated with aggressive pituitary tumors.Design and methodsCase series with germline screening of AIP and haplotype analyses among R271W families.ResultsThis previously unreported kindred consisted of three affected individuals that either presented with or had first symptoms of a pituitary macroadenoma in late childhood or adolescence. The index case, a 15-year-old male with incipient gigantism and his maternal aunt, had somatotropinomas, and the maternal uncle of the index case had a prolactinoma. All tumors were large (15, 40, and 60 mm maximum diameter) and two required transcranial surgery and radiotherapy. All three affected subjects and ten other unaffected relatives were found to be positive for a germline R271W AIP mutation. Comparison of the single nucleotide polymorphism patterns among this family and two previously reported European FIPA families with the same R271W mutation demonstrated no common ancestry.ConclusionsThis kindred exemplifies the aggressive features of pituitary adenomas associated with AIP mutations, while genetic analyses among three R271W FIPA families indicate that R271W represents a mutational hotspot that should be studied further in functional studies.

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Allen, Simon, Adel M. Abuzenadah, Joanna Hinks, Joanna L. Blagg, Turkiz Gursel, Jørgen Ingerslev, Anne C. Goodeve, Ian R. Peake, and Martina E. Daly. "A novel von Willebrand disease–causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion." Blood 96, no. 2 (July 15, 2000): 560–68. http://dx.doi.org/10.1182/blood.v96.2.560.

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Abstract In this report we describe the molecular defect underlying partial and severe quantitative von Willebrand factor (VWF) deficiencies in 3 families previously diagnosed with types 1 and 3 Von Willebrand-disease. Analysis of the VWF gene in affected family members revealed a novel C to T transition at nucleotide 1067 of the VWF complemetary DNA (cDNA), predicting substitution of arginine by tryptophan at amino acid position 273 (R273W) of pre–pro-VWF. Two patients, homozygous for the R273W mutation, had a partial VWF deficiency (VWF:Ag levels of 0.06 IU/mL and 0.09 IU/mL) and lacked high-molecular weight VWF multimers in plasma. A third patient, also homozygous for the R273W mutation, had a severe VWF deficiency (VWF:Ag level of less than 0.01 IU/mL) and undetectable VWF multimers in plasma. Recombinant VWF having the R273W mutation was expressed in COS-7 cells. Pulse-chase experiments showed that secretion of rVWFR273W was severely impaired compared with wild-type rVWF. However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). Multimer analysis showed that rVWFR273W failed to form high-molecular-weight multimers present in wild-type rVWF. We concluded that the R273W mutation is responsible for the quantitative VWF deficiencies and aberrant multimer patterns observed in the affected family members. To identify factors that may function in the intracellular retention of rVWFR273W, we investigated the interactions of VWF expressed in COS-7 cells with molecular chaperones of the ER. The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells.

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4

Allen, Simon, Adel M. Abuzenadah, Joanna Hinks, Joanna L. Blagg, Turkiz Gursel, Jørgen Ingerslev, Anne C. Goodeve, Ian R. Peake, and Martina E. Daly. "A novel von Willebrand disease–causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion." Blood 96, no. 2 (July 15, 2000): 560–68. http://dx.doi.org/10.1182/blood.v96.2.560.014k01_560_568.

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In this report we describe the molecular defect underlying partial and severe quantitative von Willebrand factor (VWF) deficiencies in 3 families previously diagnosed with types 1 and 3 Von Willebrand-disease. Analysis of the VWF gene in affected family members revealed a novel C to T transition at nucleotide 1067 of the VWF complemetary DNA (cDNA), predicting substitution of arginine by tryptophan at amino acid position 273 (R273W) of pre–pro-VWF. Two patients, homozygous for the R273W mutation, had a partial VWF deficiency (VWF:Ag levels of 0.06 IU/mL and 0.09 IU/mL) and lacked high-molecular weight VWF multimers in plasma. A third patient, also homozygous for the R273W mutation, had a severe VWF deficiency (VWF:Ag level of less than 0.01 IU/mL) and undetectable VWF multimers in plasma. Recombinant VWF having the R273W mutation was expressed in COS-7 cells. Pulse-chase experiments showed that secretion of rVWFR273W was severely impaired compared with wild-type rVWF. However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). Multimer analysis showed that rVWFR273W failed to form high-molecular-weight multimers present in wild-type rVWF. We concluded that the R273W mutation is responsible for the quantitative VWF deficiencies and aberrant multimer patterns observed in the affected family members. To identify factors that may function in the intracellular retention of rVWFR273W, we investigated the interactions of VWF expressed in COS-7 cells with molecular chaperones of the ER. The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells.

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5

Tamaura, Moe, Naoko Satoh-Takayama, Miyuki Tsumura, Takaharu Sasaki, Satoshi Goda, Tomoko Kageyama, Seiichi Hayakawa, et al. "Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice." International Immunology 32, no. 4 (December 23, 2019): 259–72. http://dx.doi.org/10.1093/intimm/dxz079.

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Abstract Gain-of-function (GOF) mutations in the gene for signal transducer and activator of transcription 1 (STAT1) account for approximately one-half of patients with chronic mucocutaneous candidiasis (CMC) disease. Patients with GOF-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to CMC, and those with severe infections and/or autoimmunity have a poor prognosis. The establishment of safe and effective treatments based on a precise understanding of the molecular mechanisms of this disorder is required to improve patient care. To tackle this problem, we introduced the human R274Q GOF mutation into mice [GOF-Stat1 knock-in (GOF-Stat1R274Q)]. To investigate the immune responses, we focused on the small intestine (SI), which contains abundant Th17 cells. Stat1R274Q/R274Q mice showed excess phosphorylation of STAT1 in CD4+ T cells upon IFN-γ stimulation, consistent with the human phenotype in patients with the R274Q mutation. We identified two subpopulations of CD4+ T cells, those with ‘normal’ or ‘high’ level of basal STAT1 protein in Stat1R274Q/R274Q mice. Upon IFN-γ stimulation, the ‘normal’ level CD4+ T cells were more efficiently phosphorylated than those from WT mice, whereas the ‘high’ level CD4+ T cells were not, suggesting that the level of STAT1 protein does not directly correlate with the level of pSTAT1 in the SI. Inoculation of Stat1R274Q/R274Q mice with Candida albicans elicited decreased IL-17-producing CD4+RORγt+ cells. Stat1R274Q/R274Q mice also excreted larger amounts of C. albicans DNA in their feces than control mice. Under these conditions, there was up-regulation of T-bet in CD4+ T cells. GOF-Stat1R274Q mice thus should be a valuable model for functional analysis of this disorder.

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6

Lafrenière, Jacynthe, Catherine Laramée, Julie Robitaille, Benoît Lamarche, and Simone Lemieux. "Assessing the relative validity of a new, web-based, self-administered 24 h dietary recall in a French-Canadian population." Public Health Nutrition 21, no. 15 (July 6, 2018): 2744–52. http://dx.doi.org/10.1017/s1368980018001611.

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AbstractObjectiveTo assess the relative validity of a new, web-based, self-administered 24 h dietary recall, the R24W, for assessment of energy and nutrient intakes among French Canadians.DesignEach participant completed a 3d food record (FR) and the R24W on three occasions over a 4-week period. Intakes of energy and of twenty-four selected nutrients assessed by both methods were compared.SettingQuébec City metropolitan area.SubjectsFifty-seven women and fifty men (mean (sd) age: 47·2 (13·3) years).ResultsEquivalent proportions of under-reporters were found with the R24W (15·0%) and the FR (23·4%). Mean (sd) energy intake from the R24W was 7·2% higher than that from the FR (10 857 (3184) kJ/d (2595 (761) kcal/d) v. 10 075 (2971) kJ/d (2408 (710) kcal/d); P<0·01). Significant differences in mean nutrient intakes between the R24W and the FR ranged from –54·8% (i.e. lower value with R24W) for niacin to +40·0% (i.e. higher value with R24W) for alcohol. Sex- and energy-adjusted deattenuated correlations between the two methods were significant for all nutrients except Zn (range: 0·35–0·72; P<0·01). Cross-classification demonstrated that 40·0% of participants were classified in the same quartile with both methods, while 40·0% were classified in the adjacent quartile and only 3·6% were grossly misclassified (1st v. 4th quartile). Analysis of Bland–Altman plots revealed proportional bias between the two assessment methods for 8/24 nutrients.ConclusionsThese data suggest that the R24W presents an acceptable relative validity as compared with the FR for estimating usual dietary intakes in a cohort of French Canadians.

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Jalnapurkar, Sapana S., Aishwarya Pawar, Patrick Somers, Gabrielle Ochoco, Subin S. George, Maxim Pimkin, and Vikram R. Paralkar. "PHF6 Restricts AML Acceleration By Promoting Myeloid Differentiation Genes in Leukemic Cells." Blood 136, Supplement 1 (November 5, 2020): 42–43. http://dx.doi.org/10.1182/blood-2020-137134.

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Acute myeloid leukemia is caused by the accumulation of mutations in hematopoietic stem and myeloid progenitor cells, resulting in increased self-renewal, inhibition of differentiation, and aberrant proliferation. Although genomic studies have comprehensively identified genes that are mutated in acute leukemias, the functional roles of many of them, and the consequences of their mutations, remain poorly understood. PHF6 (PHD-finger protein 6) is an X-linked gene that is mutated in 3.2% of de novo AML, 4.7% CMML, 3% MDS, and 1.6% CML patients. Two-thirds of somatic mutations in PHF6 are frameshift and nonsense mutations distributed throughout the gene body, resulting in loss of PHF6 protein. One-third of the mutations are point mutations clustered in the ePHD2 (extended PHD) domain, and the consequence of these mutations on PHF6 function is unknown. The functional role of PHF6 and the mechanism by which PHF6 mutations accelerate AML has not yet been determined. In this study, we delineate the cellular and molecular function of PHF6 in AML using in vitro and in vivo models. In agreement with recently published reports, we found that pan-hematopoietic deletion of Phf6 using the Vav-Cre recombinase system gave competitive transplantation advantage to HSCs, with sustained multi-lineage reconstitution without exhaustion over three rounds of serial transplantations, demonstrating that Phf6 represses HSC self-renewal. However, loss of Phf6 alone was insufficient to cause hematopoietic malignancy in the mouse model when monitored for one year. To determine the function of PHF6 in AML progression, we transduced cKO (Vav-Cre; Phf6 flox) or WT (Vav-Cre only) bone marrow cells with MSCV retrovirus expressing HOXA9 (WT+HOXA9 and cKO+HOXA9), and transplanted into irradiated recipient mice. The resulting HOXA9-driven AML was greatly accelerated in the Phf6 cKO background, with recipient mice succumbing faster (median survival 119 days) as compared to recipients transduced with HOXA9-transduced WT cells (median survival >180 days, p=0.003) (Fig 1A). This was also reflected by an increase in the number of circulating immature leukemic cells in peripheral blood at earlier timepoints. HOXA9-transduced cKO cells showed higher serial replating ability in an in vitro colony forming assay as compared with HOXA9-transduced WT cells (Fig 1B). We further investigated the molecular function of PHF6 using the THP-1 human AML cell line. PHF6 is a chromatin-binding protein with two ePHD domains, and its binding partners and pattern of chromatin occupancy are unclear. Using ChIP-Seq, we identified that PHF6 occupies enhancers, and its peaks show striking alignment with the peaks of the key myeloid transcription factors (TFs) RUNX1, PU.1, and IRF8 (Fig 1C). To assess the effect of the clinically relevant point mutation R274Q (in the ePHD2 domain) on the transcriptional effects produced by PHF6, we first generated a PHF6 KO clone from the THP-1 cell line, and then re-expressed either WT PHF6 or R274Q-mutant PHF6 in this KO line. Re-expression of WT PHF6 rescued the extensive gene expression changes produced by its knockout, but R274Q-mutant PHF6 was unable to produce any gene expression changes, indicating that it is a "transcriptionally dead" mutant (Fig 1D). Gene Ontology analysis of transcriptome changes induced by WT PHF6 showed that PHF6 promotes the expression of myeloid differentiation gene sets. In summary, PHF6 restricts AML progression by binding enhancers with key myeloid TFs, and promoting the expression of myeloid differentiation genes. R274Q mutation renders PHF6 unable to exert any downstream expression changes, indicating that the ePHD2 domain (where R274 is located, clustered with other amino acids showing point mutations in hematopoietic malignancies) is critical for PHF6 function, and likely mediates important functional interactions with chromatin partners. Our future work will involve dissection of the sequence of molecular events governed by PHF6 following enhancer occupancy, and the role of PHF6 in repressing AML self-renewal and promoting differentiation. Disclosures No relevant conflicts of interest to declare.

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Laramée, Catherine, Simone Lemieux, Julie Robitaille, and Benoît Lamarche. "Comparing the Usability of the Web-Based 24-h Dietary Recall R24W and ASA24-Canada-2018 among French-Speaking Adults from Québec." Nutrients 14, no. 21 (October 28, 2022): 4543. http://dx.doi.org/10.3390/nu14214543.

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Automated, self-administered, Web-based 24-h dietary recall tools are increasingly available for nutrition research in different settings, particularly in epidemiological studies and national surveys because of their practicality and efficiency. However, the usability of different 24-h dietary recall tools must be assessed and compared for use in specific populations as it is a major driver of the response rate and retention of participants. The primary aim of this study was to compare the usability of two validated, self-administered, web-based 24-h dietary recall tools available for the Canadian population: the R24W and the 2018 Canadian version of the ASA24. The R24W was developed in French for primary use in the province of Québec, Canada while the ASA24 was developed in English for primary use in the USA and recently adapted and translated for use in French-speaking Canadian adults. Whether the R24W and the ASA24-Canada-2018 yield similar nutritional data was also tested. In this randomized crossover study, 48 women and 20 men (mean age of 35 ± 14 years; range: 19–79 years) recruited in the province of Quebec completed the R24W and the ASA24-Canada-2018 in French twice on each occasion. Participants also completed the System Usability Scale (SUS), a reliable and valid scale giving a global view of subjective assessments of usability. Mean SUS score as well as mean dietary intakes of energy, nutrients and food groups generated by each tool were compared using mixed model analyses for repeated measures. On a scale of 0 to 100, the mean SUS scores (±SD) for the R24W and the ASA24-Canada-2018 were 81 ± 2 and 58 ± 2, respectively (p < 0.0001). 84% of participants stated that they would prefer to use the R24W if they were invited to complete additional 24-h dietary recalls. No significant difference was found between the R24W and the ASA24-Canada-2018 for the intake of energy, proteins, lipids, saturated fatty acids, carbohydrates, fibers, sodium and vegetables and fruits. In sum, while the R24W and the ASA24-Canada-2018 generate comparable self-reported dietary intake data, the R24W showed a better usability than the ASA24-Canada-2018 in a sample of French-speaking adults from the province of Quebec.

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Paradis, Frédérique, Benoît Lamarche, Julie Robitaille, Charles Couillard, Jacynthe Lafrenière, André J. Tremblay, Louise Corneau, and Simone Lemieux. "Validation of an automated self-administered 24-hour dietary recall web application against urinary recovery biomarkers in a sample of French-speaking adults of the province of Québec, Canada." Applied Physiology, Nutrition, and Metabolism 47, no. 2 (February 2022): 173–82. http://dx.doi.org/10.1139/apnm-2021-0445.

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The objective of this study was to validate an automated self-administered 24-hour dietary recall web application (R24W) against recovery biomarkers for sodium, potassium and protein intakes and to identify individual characteristics associated with misreporting in a sample of 61 men and 69 women aged 20–65 years from Québec City, Canada. Each participant completed 3 dietary recalls using the R24W, provided two 24-hour urinary samples and completed questionnaires to document psychosocial factors. Mean reported intakes were 2.2%, 2.1% and 5.0% lower than the urinary reference values, respectively, for sodium, potassium and proteins (significant difference for proteins only (p = 0.04)). Deattenuated correlations between the self-reported intake and biomarkers were significant for sodium (r = 0.48), potassium (r = 0.56) and proteins (r = 0.68). Cross-classification showed that 39.7% (sodium), 42.9% (potassium) and 42.1% (proteins) of participants were ranked into the same quartile with both methods and only 4.8% (sodium), 3.2% (potassium) and 0.8% (proteins) were ranked in opposite quartiles. Lower body esteem related to appearance was associated with sodium underreporting in women (r = 0.33, p = 0.006). No other individual factor was found to be associated with misreporting. These results suggest that the R24W has a good validity for the assessment of sodium, potassium and protein intakes in a sample of French-speaking adults. Novelty: The validity of an automated self-administered 24-hour dietary recall web application named the R24W was tested using urinary biomarkers. According to 7 criteria, the R24W was found to have a good validity to assess self-reported intakes of sodium, potassium and proteins.

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Andolfo, Immacolata, Roberta Russo, Francesco Manna, Marica Lisa Salve, Alok K. Sharma, Seth L. Alper, Lucia De Franceschi, and Achille Iolascon. "Detection of Familial Pseudohyperkalemia Among Italian Blood Donors By Genetic Screening for the R276W Mutation in ABCB6." Blood 126, no. 23 (December 3, 2015): 2132. http://dx.doi.org/10.1182/blood.v126.23.2132.2132.

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Abstract Introduction Isolated Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by cold-induced slow 'passive leak' of red cell K+ into plasma, first described in a large Scottish family from Edinburgh (Stewart GW, et al., 1979). Although in freshly obtained blood samples plasma [K+] was normal, it was increased when measured in blood stored at or below room temperature. This trait was accompanied by mild abnormalities of red cell shape. Functional gene mapping and sequencing analysis of the candidate genes within the 2q35-q36 critical interval in three multigenerational FP families with 20 affected individuals identified two novel heterozygous missense mutations in the ABCB6 gene that cosegregated with disease phenotype (Andolfo I. et al., 2013). The two genomic substitutions altered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that in erythrocyte membranes bears the Langereis blood group antigen system (Krishnamurthy PC, et al., 2006; Helias V, et al., 2012). Recently, the ABCB6 mutation R723Q was found in two patients with FP (Bawazir W, et al.,2014). Of note, both patients presented as blood donors, and increased cold-induced potassium leak was demonstrated. The transfusion of pseudohyperkalemic blood has clinical implications especially for neonates and infants receiving large-volume RBC transfusions. In this study we analyzed one additional family and report the first functional characterization of an ABCB6 mutation, towards understanding the pathogenic mechanism of FP. Moreover, we screened an Italian blood donor population for the R276W variant of the ABCB6 gene. Methods DNA was obtained for genetic analysis from affected and unaffected family members, after signed informed consent, according to the Declaration of Helsinki. The search for mutations was performed by direct sequencing of the ABCB6 gene. cDNAs encoding full-length wildtype ABCB6 were cloned into pcDNA3.1. Our patients' novel point mutation (c.826C>T, p.R276W) was introduced into pcDNA3.1-ABCB6 by site-directed mutagenesis. WT and mutant constructs were transfected into HEK-293 cells and the cells were maintained at 30°C for 72 hrs to evaluate the effects of reduced temperature. After transfection, the cells were incubated in a medium containing 86rubidium (86Rb+) as a surrogate for K+. 86Rb+ was determined in cell lysate, and K content of extracellular medium was determined by atomic absorption spectrometry. Results We found the heterozygous mutation c.826G>T, p. R276W in an Irish family. This mutation is annotated in public databases as single nucleotide variants (SNVs), and is predicted by PolyPhen2 and SIFT to be damaging. Variant R276W showed a minor allele frequency (MAF) of 1.3:100 confirming that many patients with FP could be present in the blood donor population. R276W and previously identified ABCB6 variants R375Q and R375Wwere overexpressed in HEK-293 cells to characterize the functional properties of these variants. Expression of ABCB6 mutants showed no change in RNA or polypeptide levels. However, measurement of ouabain- and bumetanide-resistant net cation flux demonstrated a greater loss of cell K from mutant ABCB6-expressing cells than from WT ABCB6-expressing cells. The high allele frequency of ABCB6 variant R276W prompted a genetic screen of 327 blood donors. The variant was present in 0.3% (1/327) of the donor cohort, and this single subject with ABCB6 R276W exhibited slightly increased MCV and variably increased plasma K+ concentrations. Conclusions: Our findings demonstrate that missense mutations in ABCB6 lead to increased K+ efflux from RBCs in FP patients. Storage of FP blood can cause a significant increase in blood K+ levels, with especially serious clinical implications for neonates and infants receiving large-volume transfusions of whole blood. Furthermore, the prevalence of FP might be underestimated, since patients with FP can be asymptomatic and thus undetected in the donor population. Screening for the most frequent ABCB6 variation, R276W, confirmed that FP patients are present in the Italian blood donor population. In the future, genetic tests for FP could be added to blood donor prescreening to improve the quality and safety of donor units. Disclosures No relevant conflicts of interest to declare.

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Aarskog, D., H. G. Eiken, R. Bjerknes, and O. L. Myking. "Pituitary dwarfism in the R271W Pit-1 gene mutation." European Journal of Pediatrics 156, no. 11 (October 1997): 829–34. http://dx.doi.org/10.1007/s004310050722.

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12

Kumar, K. M., P. Lavanya, Anand Anbarasu та Sudha Ramaiah. "Molecular dynamics and molecular docking studies on E166A point mutant, R274N/R276N double mutant, and E166A/R274N/R276N triple mutant forms of class A β-lactamases". Journal of Biomolecular Structure and Dynamics 32, № 12 (21 листопада 2013): 1953–68. http://dx.doi.org/10.1080/07391102.2013.847804.

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MORIZONO, Hiroki, Mendel TUCHMAN, Basavapatna S. RAJAGOPAL, Mark T. McCANN, Chad D. LISTROM, Xiaoling YUAN, Divakaramenon VENUGOPAL, George BARANY, and Norma M. ALLEWELL. "Expression, purification and kinetic characterization of wild-type human ornithine transcarbamylase and a recurrent mutant that produces ‘late onset’ hyperammonaemia." Biochemical Journal 322, no. 2 (March 1, 1997): 625–31. http://dx.doi.org/10.1042/bj3220625.

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Ornithine Transcarbamylase Deficiency, an X-linked disorder, is the most common cause of inherited urea cycle disorders. Approx. 90 mutations that produce reduced levels of ornithine transcarbamylase (OTCase) activity have been identified in patients [Tuchman (1993) Hum. Mutat. 2, 174–178; Tuchman and Plante (1995) Hum. Mutat. 5, 293–295]. A model of the three-dimensional structure of OTCase, developed on the basis of its homology to the catalytic subunit of Escherichia coli aspartate transcarbamylase (ATCase) [Tuchman, Morizono, Reish, Yuan and Allewell (1995) J. Med. Genet. 32, 680–688], and in good agreement with the crystal structure of Pseudomonas aeruginosa OTCase [Villeret, Tricot, Stalon and Dideberg (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10762–10766], indicates that many mutations that produce severe clinical symptoms are at the active site or buried in the interior of the protein. However, one of the few recurrent mutations, R277W, an alteration that produces a milder phenotype of ornithine transcarbamylase deficiency, is located in the model in a loop remote from the active site that is analogous to a similar loop (the 240's loop, a flexible loop of the catalytic chain of Escherichia coliaspartate transcarbamylase, comprised of residues 230–250) of ATCase. Human wild-type OTCase and the R277W mutant have been cloned and overexpressed in E. coli and a rapid and efficient purification method utilizing the bisubstrate analogue, NΔ-(phosphonacetyl)-l-ornithine, has been developed and used to purify both proteins. Gel chromatography indicates both are trimeric. The pH dependence of the kinetic parameters of the wild-type enzyme is similar to that of E. coli OTCase [Kuo, Herzberg and Lipscomb (1985) Biochemistry 24, 4754–4761], suggesting that its catalytic mechanism is similar, although its maximal activity is approx. 10-fold less. Compared with the wild-type, the R277W mutant has nearly 70-fold lower affinity for l-ornithine, shows no substrate inhibition, and its thermal stability is reduced by 5 °C. Its reduced affinity for l-ornithine, which in turn results in lower activity at physiological concentrations of ornithine, as well as its reduced stability, may contribute to the clinical effects that it produces.

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Pawar, Aishwarya, Patrick Somers, Roman Verner, Charles Antony, Subin S. George, Maxim Pimkin, and Vikram R. Paralkar. "PHF6 Positively Regulates Transcription of Myeloid Differentiation Genes By Binding at Enhancer Regions." Blood 138, Supplement 1 (November 5, 2021): 3303. http://dx.doi.org/10.1182/blood-2021-151490.

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Abstract Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by uncontrolled division, and differentiation arrest, of hematopoietic stem cells (HSCs) and myeloid progenitors. AML is a genetically heterogeneous disease, with mutations in genes belonging to multiple functional groups. Of these, chromatin regulators and transcriptional factors (TFs) are an important functional group to study because of a lack of targeted AML therapies against these factors. PHD Finger Protein 6 (PHF6) is one such chromatin-associated protein with a yet-unknown molecular mechanism of action. It is mutated in 3-5% of MDS, CMML, and AMLs and 20% of T- ALLs, and is considered a leukemia suppressor. To assess the effects of PHF6 on the AML transcriptome, we generated CRISPR-mediated knockout (KO) clones in THP-1 monocytic AML cell line, and integrated a Dox-inducible PHF6 construct into a PHF6 KO clone, enabling us to conditionally rescue PHF6 expression to parental levels (Fig A & B). RNA-Seq analysis of these knockout and rescue systems revealed that PHF6 expression upregulates genes related to myeloid differentiation and downregulates genes related to hematopoietic stem cells and cell division in myeloid cells. Additionally, loss of PHF6 increased THP-1 proliferation, and restoring PHF6 expression decreased proliferation. We also performed ChIP-Seq for PHF6 in the THP-1 cells and found that PHF6 binds to open and active enhancer regions. Unbiased motif analysis showed that PHF6-bound enhancers (compared to all enhancers genome-wide) were enriched for RUNX1, PU.1, and IRF8 motifs. Metagene plotting of PHF6 ChIP-Seq signal against ChIP-Seq for these TFs showed striking concordance in their binding patterns, indicating that PHF6 co-occupies chromatin with key hematopoietic transcription factors. (Fig C). PHF6 has two extended PHD (ePHD) domains with a similar structure to canonical PHD domains, but with unknown functions. Based on leukemia genome sequencing results from COSMIC, we observed that while nonsense and frameshift mutations of PHF6 (accounting for 2/3 rd of PHF6 mutations, and expected to produce no protein) are distributed throughout the gene body, missense mutations (accounting for 1/3 rd of PHF6 mutations and expected to produce a full-length protein with single amino acid substitution), are concentrated in the second ePHD domain (ePHD2). To assess the functional consequence of mutations in the ePHD2 domain, we generated from a PHF6 KO clone a clone expressing Dox-inducible PHF6 R274Q, the most common missense mutation of PHF6 seen in leukemia. RNA-Seq showed that PHF6 R274Q induction has no downstream effects on the cellular transcriptome, in striking contrast to the effects of wildtype PHF6 induction (Fig D). Additionally, the expression of PHF6 R274Q has no effect on cell growth. These results indicate that the ePHD2-domain mutant PHF6 R274Q is functionally dead (fully or partially), and the ePHD2 domain is critical for PHF6 function. Our results support an important transcriptional role of PHF6 in the myeloid system, involving co-occupancy with TFs at enhancers to promote the transcription of myeloid differentiation genes. This loss of this transcriptional regulation, either through complete PHF6 protein loss or point mutation of its ePHD2 domain, dysregulates myeloid differentiation and contributes to leukemogenesis. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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15

Wang, C., R. Lu, X. Ouyang, M. W. L. Ho, W. Chia, F. Yu, and K. L. Lim. "Drosophila Overexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities." Journal of Neuroscience 27, no. 32 (August 8, 2007): 8563–70. http://dx.doi.org/10.1523/jneurosci.0218-07.2007.

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16

Heneghan, John F., Arash Akhavein, Maria J. Salas, Boris E. Shmukler, Lawrence P. Karniski, David H. Vandorpe, and Seth L. Alper. "Regulated transport of sulfate and oxalate by SLC26A2/DTDST." American Journal of Physiology-Cell Physiology 298, no. 6 (June 2010): C1363—C1375. http://dx.doi.org/10.1152/ajpcell.00004.2010.

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Nephrolithiasis in the Slc26a6−/− mouse is accompanied by 50–75% reduction in intestinal oxalate secretion with unchanged intestinal oxalate absorption. The molecular identities of enterocyte pathways for oxalate absorption and for Slc26a6-independent oxalate secretion remain undefined. The reported intestinal expression of SO42− transporter SLC26A2 prompted us to characterize transport of oxalate and other anions by human SLC26A2 and mouse Slc26a2 expressed in Xenopus oocytes. We found that hSLC26A2-mediated [14C]oxalate uptake ( K1/2 of 0.65 ± 0.08 mM) was cis-inhibited by external SO42− ( K1/2 of 3.1 mM). hSLC26A2-mediated bidirectional oxalate/SO42− exchange exhibited extracellular SO42− K1/2 of 1.58 ± 0.44 mM for exchange with intracellular [14C]oxalate, and extracellular oxalate K1/2 of 0.14 ± 0.11 mM for exchange with intracellular 35SO42−. Influx rates and K1/2 values for mSlc26a2 were similar. hSLC26A2-mediated oxalate/Cl− exchange and bidirectional SO42−/Cl− exchange were not detectably electrogenic. Both SLC26A2 orthologs exhibited nonsaturable extracellular Cl− dependence for efflux of intracellular [14C]oxalate, 35SO42−, or 36Cl−. Rate constants for 36Cl− efflux into extracellular Cl−, SO42−, and oxalate were uniformly 10-fold lower than for oppositely directed exchange. Acidic extracellular pH (pHo) inhibited all modes of hSLC26A2-mediated anion exchange. In contrast, acidic intracellular pH (pHi) selectively activated exchange of extracellular Cl− for intracellular 35SO42− but not for intracellular 36Cl− or [14C]oxalate. Protein kinase C inhibited hSLC26A2 by reducing its surface abundance. Diastrophic dysplasia mutants R279W and A386V of hSLC26A2 exhibited similar reductions in uptake of both 35SO42− and [14C]oxalate. A386V surface abundance was reduced, but R279W surface abundance was at wild-type levels.

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17

Ballhausen, D. "Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W." Journal of Medical Genetics 40, no. 1 (January 1, 2003): 65–71. http://dx.doi.org/10.1136/jmg.40.1.65.

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18

Ward, Tarsha, Warren Tai, Sarah Morton, Francis Impens, Petra Van Damme, Delphi Van Haver, Evy Timmerman, et al. "Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency." Circulation Research 128, no. 8 (April 16, 2021): 1156–69. http://dx.doi.org/10.1161/circresaha.120.316966.

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Rationale: NAA15 (N-alpha-acetyltransferase 15) is a component of the NatA (N-terminal acetyltransferase complex). The mechanism by which NAA15 haploinsufficiency causes congenital heart disease remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective: We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity and identifying proteins dependent upon a full amount of NAA15. Methods and Results: We introduced heterozygous loss of function, compound heterozygous, and missense residues (R276W) in iPSCs using CRISPR/Cas9. Haploinsufficient NAA15 iPSCs differentiate into cardiomyocytes, unlike NAA15 -null iPSCs, presumably due to altered composition of NatA. Mass spectrometry analyses reveal ≈80% of identified iPSC NatA targeted proteins displayed partial or complete N-terminal acetylation. Between null and haploinsufficient NAA15 cells, N-terminal acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W induced pluripotent stem cells. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; 18 were ribosomal-associated proteins. At least 4 proteins were encoded by genes known to cause autosomal dominant congenital heart disease. Conclusions: These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and N-terminal acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated congenital heart disease. Additionally, genetically engineered induced pluripotent stem cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function.

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19

Dey, Bishwajyoti, and Avinash Khare. "Stability of compacton solutions." Physical Review E 58, no. 3 (September 1, 1998): R2741—R2744. http://dx.doi.org/10.1103/physreve.58.r2741.

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20

Peschel, U., D. Michaelis, C. Etrich, and F. Lederer. "Formation, motion, and decay of vectorial cavity solitons." Physical Review E 58, no. 3 (September 1, 1998): R2745—R2748. http://dx.doi.org/10.1103/physreve.58.r2745.

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21

Marroum, Renata-Maria, Germano S. Iannacchione, Daniele Finotello, and Michael A. Lee. "Numerical study of cylindrically confined nematic liquid crystals." Physical Review E 51, no. 4 (April 1, 1995): R2743—R2746. http://dx.doi.org/10.1103/physreve.51.r2743.

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22

Scheerboom, Marcel I. M., and Jan A. Schouten. "Critical broadening of the vibrational linewidth by concentration fluctuations." Physical Review E 51, no. 4 (April 1, 1995): R2747—R2750. http://dx.doi.org/10.1103/physreve.51.r2747.

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23

Gairard, A. C., F. Adam, M. C.H.auvin, D. Le Bars, and F. Guirimand. "R274 La ketamine augmente la puissance du sufentanil: Etude experimentale chez le rat." Annales Françaises d'Anesthésie et de Réanimation 17, no. 8 (January 1998): 949. http://dx.doi.org/10.1016/s0750-7658(98)80393-6.

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24

He, X., J. Lobsiger, and A. Stocker. "Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W." Proceedings of the National Academy of Sciences 106, no. 44 (October 21, 2009): 18545–50. http://dx.doi.org/10.1073/pnas.0907454106.

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25

Carr, Jonathan, Ilaria Guella, Chelsea Szu-Tu, Sihaam Boolay, Brigitte Glanzmann, Matthew J. Farrer, and Soraya Bardien. "Double homozygous mutations (R275W and M432V) in the ParkinGene associated with late-onset Parkinson's disease." Movement Disorders 31, no. 3 (February 10, 2016): 423–25. http://dx.doi.org/10.1002/mds.26524.

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26

Kladova, Olga A., Irina V. Alekseeva, Murat Saparbaev, Olga S. Fedorova, and Nikita A. Kuznetsov. "Modulation of the Apurinic/Apyrimidinic Endonuclease Activity of Human APE1 and of Its Natural Polymorphic Variants by Base Excision Repair Proteins." International Journal of Molecular Sciences 21, no. 19 (September 28, 2020): 7147. http://dx.doi.org/10.3390/ijms21197147.

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Human apurinic/apyrimidinic endonuclease 1 (APE1) is known to be a critical player of the base excision repair (BER) pathway. In general, BER involves consecutive actions of DNA glycosylases, AP endonucleases, DNA polymerases, and DNA ligases. It is known that these proteins interact with APE1 either at upstream or downstream steps of BER. Therefore, we may propose that even a minor disturbance of protein–protein interactions on the DNA template reduces coordination and repair efficiency. Here, the ability of various human DNA repair enzymes (such as DNA glycosylases OGG1, UNG2, and AAG; DNA polymerase Polβ; or accessory proteins XRCC1 and PCNA) to influence the activity of wild-type (WT) APE1 and its seven natural polymorphic variants (R221C, N222H, R237A, G241R, M270T, R274Q, and P311S) was tested. Förster resonance energy transfer–based kinetic analysis of abasic site cleavage in a model DNA substrate was conducted to detect the effects of interacting proteins on the activity of WT APE1 and its single-nucleotide polymorphism (SNP) variants. The results revealed that WT APE1 activity was stimulated by almost all tested DNA repair proteins. For the SNP variants, the matters were more complicated. Analysis of two SNP variants, R237A and G241R, suggested that a positive charge in this area of the APE1 surface impairs the protein–protein interactions. In contrast, variant R221C (where the affected residue is located near the DNA-binding site) showed permanently lower activation relative to WT APE1, whereas neighboring SNP N222H did not cause a noticeable difference as compared to WT APE1. Buried substitution P311S had an inconsistent effect, whereas each substitution at the DNA-binding site, M270T and R274Q, resulted in the lowest stimulation by BER proteins. Protein–protein molecular docking was performed between repair proteins to identify amino acid residues involved in their interactions. The data uncovered differences in the effects of BER proteins on APE1, indicating an important role of protein–protein interactions in the coordination of the repair pathway.

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Fujiki, Ryoji, Atsushi Hijikata, Tsuyoshi Shirai, Satoshi Okada, Masao Kobayashi, and Osamu Ohara. "Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation." Journal of Biological Chemistry 292, no. 15 (March 3, 2017): 6240–54. http://dx.doi.org/10.1074/jbc.m116.753848.

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28

Tomanicek, Stephen J., Matthew P. Blakeley, Jonathan Cooper, Yu Chen, Pavel V. Afonine та Leighton Coates. "Neutron Diffraction Studies of a Class A β-Lactamase Toho-1 E166A/R274N/R276N Triple Mutant". Journal of Molecular Biology 396, № 4 (березень 2010): 1070–80. http://dx.doi.org/10.1016/j.jmb.2009.12.036.

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29

Schachter-Tokarz, Esther, Bruno Cassinat, Charikleia Kelaidi, Christine Chomienne, Claude Gardin, Emmanuel Raffoux, Herve Dombret, Pierre Fenaux та Robert Gallagher. "Uncommon Mutations in PML-RARα Associated with Poor Outcome after First Relapse in APL." Blood 110, № 11 (16 листопада 2007): 4248. http://dx.doi.org/10.1182/blood.v110.11.4248.4248.

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Abstract Background. Mutations in the RARα-region ligand binding domain (LBD) of PML-RARα were detected in 30 – 40% of patients (pts) tested after first relapse from ATRA-chemotherapy (CT) regimens in 2 North American Phase III trials. However, no follow-up data were reported to assess whether this affected subsequent outcome. Methods. In the current study, 8 relapse pts were tested by previously-published techniques for PML-RARα LBD mutations after relapse from ATRA-CT regimens of the EAG. Treatment was according to the APL2000 protocol: randomization to induction with ATRA+DNR with AraC (arm-A) or no AraC (arm-B) followed by 2 consolidation courses with DNR with (A) or without (B) AraC and then 2 years maintenance with ATRA for 15 days every 3 months, as well as, 6MP and MTX (Ades, et al, J Clin Oncology24, 5703, 2006); 1 off-protocol (OP) pt was treated according to APL-93, which is similar to APL2000-A (Fenaux, et al, Blood94, 1192, 1999). Results. Patient Treatment Days to Relapse Days ATRA Maintenance Days Off ATRA PML-RARα LBD Mutation Status Post-Relapse 1-Au APL2000-B 1037 120 173 No CR2 2-An OP like-A 1072 120 210 No CR2 3-Ho APL2000-A 1194 105 529 No CR2 4_Ge APL2000-B 557 90 0 del/ins & R276W Rel1→Dead 5-Lu OP like-93 1249 0 ~1200 No Dead in CR2 6-Ro OP like-A + VP16 992 0 ~950 No CR2 7-Ka APL2000-B 530 45 0 ΔK227→S229/ M227 Rel3→Dead 8-Ma APL2000-B + AraC 406 45 0 R272W & N298S Rel2→CR3 Mutations were observed in the reported incidence range: 3/8 pts (37.5%). However, the findings were unusual, since 2/3 mutations were deletion mutations, while only 2/30 reported mutations were deletions, and since 2/3 pts harbored 2 mutant subclones, while only 1/30 such cases has been reported. Also, the nature of the mutations was unusual. In pt 7, the ΔK227∅S229/M227 mutation was atypically located in the amino-region of the LBD. In pt 4, a very atypical deletion/insertion (del/ins) mutation began in the hinge RARα-region at S157, extending 630 nt to R367, and was associated with a 547 nt insertion from the beginning of intron 4 that changed the translational reading frame, encoding a truncated protein lacking the entire LBD. Most notably, the 3 pts harboring these uncommon mutations either failed to achieve a second complete remission (CR) or suffered subsequent relapses, leading to death in 2 pts from resistant disease (pts 4 & 7), while 0/5 non-mutant pts relapsed (pt 5, death in CR2 was treatment-related). Discussion. With such a small sample size, it is not possible to determine whether the uncommon mutations occurred by chance or related to some unrecognized element in the EAG pts. No readily apparent basis could be identified: the modest treatment dose-schedule differences from other Phase III studies using common therapeutic agents seems an improbable cause; one each of the mutant/non-mutant pts had an extra chromosome (trisomy 8); 2 of the non-mutant cases had treatment-related APL. Although further study is needed to determine whether the poor outcome in 3 pts was related to the uncommon nature of their mutations, these results suggest that testing for PML-RARα mutations at first relapse may be of prognostic and potential therapeutic value.

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30

Curran-Everett, D. C., J. R. Claybaugh, K. Miki, S. K. Hong, and J. A. Krasney. "Hormonal and electrolyte responses of conscious sheep to 96 h of hypoxia." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 255, no. 2 (August 1, 1988): R274—R283. http://dx.doi.org/10.1152/ajpregu.1988.255.2.r274.

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Hypoxia alters the relationship of aldosterone secretion to plasma renin activity. The potential role plasma electrolytes play in this modification is not clear. This study analyzed the interrelationships among renin, aldosterone, vasopressin (ADH), and plasma electrolytes during 96 h of normobaric hypoxia. Eight ewes were exposed, in discrete experiments, to hypocapnic hypoxia [arterial O2 tension (PaO2) 37-42 mmHg, arterial CO2 tension (PaCO2) 26-28 mmHg] and eucapnic hypoxia (PaO2 40-43 mmHg, PaCO2 28-31 mmHg) by N2 dilution in an environmental chamber. Urine output (24 h) was measured, and arterial plasma samples were collected during the normoxic control period and at 24-h intervals of hypoxia. Plasma Na+, K+, renin, and ADH levels did not change from the normoxic values during either hypocapnic or eucapnic hypoxia. However, urinary aldosterone excretion [critical significance (alpha) less than 0.046] and K+ excretion (alpha less than 0.046) decreased markedly during each type of hypoxia. All sheep developed a pronounced negative K+ balance by 96 h of hypoxia. These data suggest that plasma K+ concentration is preserved by movement of K+ out of the intracellular compartment; this change in K+ distribution may inhibit aldosterone secretion during hypoxia.

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31

Reinhardt, H. W., U. Palm, R. Mohnhaupt, K. Dannenberg, and W. Boemke. "Computer-assisted long-term measurements of urinary output and other biological data." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 258, no. 1 (January 1, 1990): R274—R280. http://dx.doi.org/10.1152/ajpregu.1990.258.1.r274.

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A computerized system is described, combining automatic collection of urine in short intervals (minutes) over long periods (days) and recordings of body temperature, MABP, and heart rate in chronically instrumented conscious dogs. During the studies the dogs are housed in metabolic cages. Indwelling catheters and electrical wires are connected to a specially designed swivel and directed out of the cage to the next room. Infusions, blood sampling, and monitoring can be performed from this room without disturbance to the dogs. Three examples of recordings are given. In one of these examples the sodium excretion patterns on 5 consecutive days under continuous saline infusion in one dog is evaluated. Urine was collected every 20 min. Sodium excretion showed cyclic variations. Fourier analysis exhibited 18-h periods and 4- to 8-h periods. The described system renders, e.g., coherent time series analysis possible for a variety of simultaneously recorded physiological variables and may thus acquire considerable importance for integrative physiology.

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32

Hoban, T. M., and F. M. Sulzman. "Light effects on circadian timing system of a diurnal primate, the squirrel monkey." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 249, no. 2 (August 1, 1985): R274—R280. http://dx.doi.org/10.1152/ajpregu.1985.249.2.r274.

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We examined light effects on the circadian timing system of the squirrel monkey. A phase-response curve to 1-h pulses of light was constructed for the drinking rhythm of six animals. The phase-response curve was the same type as that exhibited by nocturnal rodents, with phase delays occurring early in the subjective night and phase advances late in the subjective night. The range of entrainment of 10 monkeys to days with 1 h light and x h dark was determined. Five monkeys used to generate the phase-response curve were also used in the range of entrainment determination. For short light-dark cycles the range of entrainment was smaller than that expected, with no monkey entraining to a day length of less than 23.5 h.

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33

Turton, W. E., J. Ciriello, and F. R. Calaresu. "Changes in forebrain hexokinase activity after aortic baroreceptor denervation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 251, no. 2 (August 1, 1986): R274—R281. http://dx.doi.org/10.1152/ajpregu.1986.251.2.r274.

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Although forebrain structures have been implicated in both the development and maintenance of the elevated arterial pressure (AP) after aortic baroreceptor denervation, little is known about the location of central structures involved in the hypertensive process. In the present study, regions of the forebrain whose metabolic activity was altered after aortic baroreceptor denervation were functionally identified using hexokinase (HK) histochemistry in the rat. Three days after bilateral aortic depressor nerve (ADN) transection AP was significantly elevated compared with sham ADN-transected animals (143 +/- 1 and 122 +/- 2 mmHg, respectively). Significant increases in HK activity were observed in the magno- and parvocellular components of the paraventricular nucleus of the hypothalamus, supraoptic nucleus, nucleus circularis, median preoptic nucleus, subfornical organ, and central nucleus of the amygdala in the ADN-transected animals. These data have demonstrated that removal of aortic baroreceptor afferent inputs alters the activity of forebrain structures previously implicated in regulation of body fluid balance and AP and suggest that these structures are involved in the hypertensive process after ADN transection.

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34

Grant, D. A., C. Franzini, J. Wild, and A. M. Walker. "Continuous measurement of blood flow in the superior sagittal sinus of the lamb." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 269, no. 2 (August 1, 1995): R274—R279. http://dx.doi.org/10.1152/ajpregu.1995.269.2.r274.

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We assessed the validity of recording blood flow in the superior sagittal sinus (Qss) as a measure of cerebral blood flow (CBF). While anesthetized, 10 lambs were instrumented with a transit-time ultrasonic flow probe around the superior sagittal sinus to measure Qss, electrodes to assess sleep state, catheters to measure cerebral perfusion pressure (Pcp), and an occlusive cuff around the common brachiocephalic artery to vary blood pressure. After 72 h recovery, lambs were studied during spontaneous sleep-wake cycles to establish 1) the normal range of Qss and 2) the response rate of Qss to rapid alterations of Pcp. Subsequently, the lambs were reanesthetized, and the measurement of Qss was calibrated and validated. Qss was linearly related to the arterial inflow of 35% of the brain mass (y = 0.5 x + 1.6, r = 0.93, n = 4). Qss was greater in active sleep (154.1 +/- 45.7 ml.min-1 x 100 g-1, mean +/- SD, n = 5) than in quiet sleep (97.1 +/- 40.8 ml.min-1 x 100 g-1) and quiet wakefulness (107 +/- 44.3 ml.min-1 x 100 g-1, P < 0.05). Qss responded rapidly (within one beat) to spontaneous and to induced transient changes in Pcp. We conclude that recording blood flow in the superior sagittal sinus provides a simple, continuous, and quantitative measure of CBF from a defined area of the brain and is appropriate for studying transient changes in the cerebral circulation.

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35

León-Velarde, F., M. C. Bourin, R. Germack, K. Mohammadi, B. Crozatier, and J. P. Richalet. "Differential alterations in cardiac adrenergic signaling in chronic hypoxia or norepinephrine infusion." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 280, no. 1 (January 1, 2001): R274—R281. http://dx.doi.org/10.1152/ajpregu.2001.280.1.r274.

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Norepinephrine (NE)-induced desensitization of the adrenergic receptor pathway may mimic the effects of hypoxia on cardiac adrenoceptors. The mechanisms involved in this desensitization were evaluated in male Wistar rats kept in a hypobaric chamber (380 Torr) and in rats infused with NE (0.3 mg · kg−1 · h−1) for 21 days. Because NE treatment resulted in left ventricular (LV) hypertrophy, whereas hypoxia resulted in right (RV) hypertrophy, the selective hypertrophic response of hypoxia and NE was also evaluated. In hypoxia, α1-adrenergic receptors (AR) density increased by 35%, only in the LV. In NE, α1-AR density decreased by 43% in the RV. Both hypoxia and NE decreased β-AR density. No difference was found in receptor apparent affinity. Stimulated maximal activity of adenylate cyclase decreased in both ventricles with hypoxia (LV, 41%; RV, 36%) but only in LV with NE infusion (42%). The functional activities of Gi and Gs proteins in cardiac membranes were assessed by incubation with pertussis toxin (PT) and cholera toxin (CT). PT had an important effect in abolishing the decrease in isoproterenol-induced stimulation of adenylate cyclase in hypoxia; however, pretreatment of the NE ventricle cells with PT failed to restore this stimulation. Although CT attenuates the basal activity of adenylate cyclase in the RV and the isoproterenol-stimulated activity in the LV, pretreatment of NE or hypoxic cardiac membranes with CT has a less clear effect on the adenylate cyclase pathway. The present study has demonstrated that 1) NE does not mimic the effects of hypoxia at the cellular level, i.e., hypoxia has specific effects on cardiac adrenergic signaling, and 2) changes in α- and β-adrenergic pathways are chamber specific and may depend on the type of stimulation (hypoxia or adrenergic).

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Bergeron, Amélie, Marie-Ève Labonté, Didier Brassard, Alexandra Bédard, Catherine Laramée, Julie Robitaille, Sophie Desroches, et al. "Intakes of Total, Free, and Naturally Occurring Sugars in the French-Speaking Adult Population of the Province of Québec, Canada: The PREDISE Study." Nutrients 11, no. 10 (September 30, 2019): 2317. http://dx.doi.org/10.3390/nu11102317.

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The objective of this study was to characterize the intakes of different types of sugars in an age- and sex-representative sample of French-speaking adults from five regions of the Province of Québec, Canada, enrolled in the cross-sectional PREDISE (PRÉDicteurs Individuels, Sociaux et Environnementaux) study (n = 1147, 18–65 years old; 50.2% women). Because only total sugar content of foods and beverages is available in the Canadian Nutrient File (CNF) 2015, the initial step of this study was thus to build a database of free and naturally occurring sugars content of each food item and recipe included in the R24W, which is an automated, self-administered, web-based, 24-h dietary recall validated to estimate nutrient intakes in French-speaking adults of the Province of Québec. Total sugars were manually differentiated into free and naturally occurring sugars using a systematic algorithm based on previously published systematic algorithms. The World Health Organization (WHO)’s free sugar definition was used to differentiate total sugars into free and naturally occurring sugars. Dietary intake estimates were assessed using three 24-h dietary recalls completed with the R24W. Mean total, free, and naturally occurring sugar intakes were 116.4 g (19.3% of daily energy intake (%E)), 72.5 g (11.7%E), and 44.0 g (7.5%E), respectively. Over half (57.3%) of the overall sample did not meet the WHO’s recommendation to consume less than 10%E from free sugars. Women had a higher %E from naturally occurring sugars than men and being younger was associated with a greater %E from free sugars. Sugar intakes among French-speaking adults from the Province of Québec were mainly in the form of free sugars, with the majority of the population exceeding the WHO recommendation regarding free sugar intake. This suggests that public health efforts towards reducing free sugar intake in this population are relevant and necessary, considering that overconsumption of free sugars negatively influences health outcomes.

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Cao, Zhimin, Emmanuel Petroulakis, Timothy Salo та Barbara Triggs-Raine. "BenignHEXAMutations, C739T(R247W) and C745T(R249W), Cause β-Hexosaminidase A Pseudodeficiency by Reducing the α-Subunit Protein Levels". Journal of Biological Chemistry 272, № 23 (6 червня 1997): 14975–82. http://dx.doi.org/10.1074/jbc.272.23.14975.

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38

Tasca, Giorgio, Massimiliano Mirabella, Aldobrando Broccolini, Mauro Monforte, Mario Sabatelli, Gian Luca Biscione, Giulio Piluso, et al. "An Italian case of hereditary myopathy with early respiratory failure (HMERF) not associated with the titin kinase domain R279W mutation." Neuromuscular Disorders 20, no. 11 (November 2010): 730–34. http://dx.doi.org/10.1016/j.nmd.2010.07.269.

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39

Ruffmann, Claudio, Michela Zini, Stefano Goldwurm, Manuela Bramerio, Sonia Spinello, Damiana Rusconi, Marcello Gambacorta, Fabrizio Tagliavini, Gianni Pezzoli, and Giorgio Giaccone. "Lewy body pathology and typical Parkinson disease in a patient with a heterozygous (R275W) mutation in the Parkin gene (PARK2)." Acta Neuropathologica 123, no. 6 (May 4, 2012): 901–3. http://dx.doi.org/10.1007/s00401-012-0991-7.

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Mano, Hiroki, Miyu Nishikawa, Kaori Yasuda, Shinichi Ikushiro, Nozomi Saito, Daisuke Sawada, Shinobu Honzawa, Masashi Takano, Atsushi Kittaka, and Toshiyuki Sakaki. "Novel screening system for high-affinity ligand of heredity vitamin D-resistant rickets-associated vitamin D receptor mutant R274L using bioluminescent sensor." Journal of Steroid Biochemistry and Molecular Biology 167 (March 2017): 61–66. http://dx.doi.org/10.1016/j.jsbmb.2016.11.008.

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41

Marsden, L., I. R. Peake, M. E. Daly, and S. A. Croft. "Can full-length wild-type von Willebrand factor (VWF) or the VWF propeptide rescue secretion of the R273W VWF variant associated with quantitative deficiency?" Journal of Thrombosis and Haemostasis 1 (July 2003): P1662. http://dx.doi.org/10.1111/j.1538-7836.2003.tb05757.x.

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Koika, Vasiliki, Petros Varnavas, Helen Valavani, Yisrael Sidis, Lacey Plummer, Andrew Dwyer, Richard Quinton, et al. "Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH)." Gene 516, no. 1 (March 2013): 146–51. http://dx.doi.org/10.1016/j.gene.2012.12.041.

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43

Turton, James P. G., Rachel Reynaud, Ameeta Mehta, John Torpiano, Alexandru Saveanu, Kathryn S. Woods, Anatoly Tiulpakov, et al. "Novel Mutations within the POU1F1 Gene Associated with Variable Combined Pituitary Hormone Deficiency." Journal of Clinical Endocrinology & Metabolism 90, no. 8 (August 1, 2005): 4762–70. http://dx.doi.org/10.1210/jc.2005-0570.

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Context: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency. Objective: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1. Results: Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation. Conclusions: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.

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44

Vondracek, P., M. Hermanova, H. Oslejskova, J. Soukalova, R. Gaillyova, V. Malinova, H. Poupetova, D. Halley, and A. van der Ploeg. "M.P.2.02 A family with multiple members affected by late-onset Pompe disease due to the R224W(670C>T) mutation: Potential candidates for enzyme replacement therapy?" Neuromuscular Disorders 17, no. 9-10 (October 2007): 793. http://dx.doi.org/10.1016/j.nmd.2007.06.111.

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45

Daly, Adrian F., Jean-François Vanbellinghen, Sok Kean Khoo, Marie-Lise Jaffrain-Rea, Luciana A. Naves, Mirtha A. Guitelman, Arnaud Murat, et al. "Aryl Hydrocarbon Receptor-Interacting Protein Gene Mutations in Familial Isolated Pituitary Adenomas: Analysis in 73 Families." Journal of Clinical Endocrinology & Metabolism 92, no. 5 (May 1, 2007): 1891–96. http://dx.doi.org/10.1210/jc.2006-2513.

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Abstract Context: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. Objective: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). Design: This was a multicenter, international, collaborative study. Setting: The study was conducted in 34 university endocrinology and genetics departments in nine countries. Patients: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. Main Outcome Measures: Presence/absence and description of AIP gene mutations were the main outcome measures. Intervention: There was no intervention. Results: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. Conclusions: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

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Novak, Gabriela, Steven Finkbeiner, Gaia Skibinski, Michela Bernini, Cristina Donato, and Alexander Skupin. "Generation of two human induced pluripotent stem cell lines from fibroblasts of Parkinson’s disease patients carrying the ILE368ASN mutation in PINK1 (LCSBi002) and the R275W mutation in Parkin (LCSBI004)." Stem Cell Research 61 (May 2022): 102765. http://dx.doi.org/10.1016/j.scr.2022.102765.

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Terkawi, Laila, Carmelo Gurnari, Sunisa Kongkiatkamon, Simona Pagliuca, Minako Mori, Hassan Awada, Ishani Pandit, et al. "Genomic Landscape of PHD Finger Protein 6 (PHF6) Mutant Myeloid Neoplasia." Blood 138, Supplement 1 (November 5, 2021): 1154. http://dx.doi.org/10.1182/blood-2021-153554.

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Abstract Clinical impact and mechanistic contributions to leukemogenesis are difficult to assign to less common somatic mutations. However, the genetics of inherited syndromes can often be helpful in discerning the biological functions and mechanistic consequences of genes in other diseases. PHF6 (Xq26.2) encodes a protein consisting of two PHD-type zinc finger domains with activity in transcriptional regulation. PHF6 translocations were originally described in T-ALL and its mutations were later observed also in CML and adult AML. Germline (GL) PHF6MT cause Börjeson-Forssman-Lehmann syndrome (BFLS), an X-linked disorder characterized by intellectual disability and, to date, only a few BFLS cases were found to develop lymphoma or T-ALL. While regularly encountered in myeloid neoplasia (MN), the impact and functional meaning of PHF6 are not well established. To determine the incidence, distribution and molecular context of PHF6MT we studied a large cohort of patients with MN (n=8617) collected from our institution and public series. 1 Overall, 73% of patients were AML (pAML 69%; sAML 4%), MDS (22%) and MDS/MPN (5%) with a median age at diagnosis of 67 ys (18-100). We detected 149 patients (2%) carrying at least 1 PHF6MT with 11 harboring more than 1 hit. Four patients carried -X in addition to PHF6MT (2 males; 2 females). Majority of patients (68%) carried frameshift del/ins and nonsense. Mutations were scattered across all coding region with a slightly enrichment (47%) in the second PHD domain (239-330 aa) including the frequent R274Q/X (n=17). Common hits mainly affected arginine residues essential for DNA binding capacity (R129X n=9, R116X=7, R319X=5, R225X=3) followed by other hits (I314T=6, Y301X and C20fs=4 each). Of note, R116X, R225X, R274X, C280Y, H329R and Y303* lesions overlapped with the T-ALL PHF6MT spectrum while no overlap was found with GL mutations found in BFLS. Overall, 75% of all PHF6MT carriers were males and carried mostly (80%) truncating lesions. Compared to mutational frequencies observed in other X-linked genes, truncating PHF6MT behaved similarly to those in ZRSR2 (78%), STAG2 (73%) and BCOR (62%). Conversely, BCORL1MT, KDM6AMT and PIGAMT were evenly distributed between genders. When evaluating mutational characteristics in males and females, no differences were found in sex-adjusted median variant allelic burden of PHF6MT (54.8 vs 51%) nor its mRNA expression levels suggesting locus inactivation. PHF6MT tended to be older than PHF6WT patients (72 vs 68 ys; P= .05) and had mostly (63%) AML followed by MDS (23%) and MDS/MPN (14%). OS was similar between PHF6MT and PHF6WT patients (P= .16). Expression analyses showed that PHF6 loss leads to deregulation of chromatin and transcriptional factor genes. Indeed, in our cohort the most comutated genes were transcriptional factors and chromatin modifiers genes such as RUNX1 (26/149, 17%), ASXL1 (23/149, 15%) and TET2 (17/149, 11%). Of note, this group characterized by the triple ASXL1, RUNX1, TET2 mutational configuration clustered in one of the genomic groups previously identified (GC-3) 1 but the presence of these lesions did not worsen the OS as compared to PHF6MT without this mutational constellation. A low frequency of SF3B1MT (4%) was also noted confirming the enrichment of PHF6MT in AML rather than in low risk MDS. Further, 12% (14 males; 4 females) of PHF6MT patients had X-mutation mosaicism as shown by concomitant hits in BCOR (n=8), ZRSR2 (4), STAG2 (5), KDM6A (1). PHF6MT were equally founder lesions (30%; 44/149) and subclonal (34%; 50/149) whereas the rest was indistinguishable by VAF discrimination (co-dominant). The most common subclonal mutations were U2AF1 (14%, 6/44), IDH1/2 (9%, 4/44) and RUNX1 (7%, 3/44). When PHF6MT were subclonal, the founder hits were in TET2 (14%, 7/50), DNMT3A and RUNX1 (12%, each 6/50) genes. Given the high frequency of RUNX1MT in PHF6MT we investigated whether RUNX1 and PHF6 might be correlated. Transcriptomic analysis of 6246 patients (from 9 public studies) 2 showed a direct linear correlation (AdjR2= .03, P=5.55e-05) between the expression of the two genes. Our study is the largest to date to investigate the genetic landscape of PHF6MT in MN and highlights a strong connection of PHF6 with transcriptional regulation and chromatin genes. Ongoing scDNA-seq will clarify whether these mutations were acquired in distinct clones helping in dissecting the clonal hierarchy of PHF6MT cases. Disclosures Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Takeda: Other: Independent review committee; Astex: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Advani: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Research Funding; Immunogen: Research Funding; OBI: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding. Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Alexion: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.

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da Costa, Marianges Zadrozny Gouvêa, Júlia Glória Lucatelli Pires, Paulo Dominguez Nasser, Camila da Silva Ferreira, Ana Cristina de Sá Teixeira, Denise Cerqueira Paranaguá-Vezozzo, Dulce Reis Guarita, Flair José Carrilho, and Suzane Kioko Ono. "Frequency of Tabagism and N34S and P55S Mutations of Serine Peptidase Inhibitor, Kazal Type 1 (SPINK1) and R254W Mutation of Chymotrypsin C (CTRC) in Patients With Chronic Pancreatitis and Controls." Pancreas 45, no. 9 (October 2016): 1330–35. http://dx.doi.org/10.1097/mpa.0000000000000650.

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49

Rochefort, Gabrielle, Didier Brassard, Julie Robitaille, Véronique Provencher, Simone Lemieux, and Benoît Lamarche. "Transitioning to Sustainable Dietary Patterns: Learnings From the Dietary Patterns of Adults With Low Animal Protein Consumption in the Province of Quebec." Current Developments in Nutrition 6, Supplement_1 (June 2022): 396. http://dx.doi.org/10.1093/cdn/nzac054.051.

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Abstract Objectives The sustainable diet paradigm rests, among others, on the replacement of animal proteins by plant-based proteins. Our aim was to provide insights on the food and nutrient characteristics of a dietary pattern consistent with lower intakes of animal proteins among French Canadians. Methods Analyses were conducted in 1147 French-speaking adults (50.2% female, mean age 42.8y) of the PRÉDicteurs Individuels, Sociaux et Environnementaux (PREDISE) study in Québec. Dietary intakes were evaluated using a validated web-based 24hr dietary recall (R24W) repeated on three unannounced occasions. Foods were classified according to the 2019 Canada's Food Guide (CFG) food categories and consumption was expressed as reference amount (RA) or nutrient amounts (in g or mg) per 2000kcal. Diet quality was assessed using the Healthy Eating Food Index-2019, a new index that reflects adherence to the recommendations on healthy food choices in 2019 CFG. Animal protein consumption was classified into quartiles and differences in food and nutrient intakes as well as in the HEFI-2019 score between quartiles were assessed using linear regression models adjusted for age and sex as well as for multiple comparisons. Results Compared with those in the highest quartile of animal protein consumption, participants in the lowest quartile reported consuming more plant-based protein foods (+0.4 RA/2000 kcal; 95%CI 0.2;0.6), refined grains (+0.3 RA/2000 kcal; 95% CI 0.1;0.5), foods not recommended in CFG 2019 (+1.5 RA/2000 kcal; 95%CI 1.0;2.0), polyunsaturated fatty acids (+2.5g/2000 kcal; 95%CI 1.4;3.5) and free sugars (+20.0g/2000 kcal; 95%CI 14.0;26.0). They also consumed less monounsaturated fatty acids (−1.8g/2000 kcal; 95%CI −3.2; −0.4), saturated fats (−7.3g/2000 kcal; 95%CI −8.8; −5.9) and sodium (-349 mg/2000 kcal; 95%CI -510; -188). The HEFI-2019 score was similar among quartiles of animal protein consumption. Conclusions The dietary pattern of French-Canadian adults who consume lesser amounts of animal proteins is not entirely consistent with better diet quality. These results highlight some of the challenges in transitioning the dietary habits of French Canadian adults into more sustainable and healthier patterns. Funding Sources Canadian Institute for Health Research, Centre Nutrition, Santé et Société-NUTRISS and Fonds de nutrition publique.

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Tan, Manuela M. X., Naveed Malek, Michael A. Lawton, Leon Hubbard, Alan M. Pittman, Theresita Joseph, Jason Hehir, et al. "Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study." Brain 142, no. 9 (July 19, 2019): 2828–44. http://dx.doi.org/10.1093/brain/awz191.

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AbstractOur objective was to define the prevalence and clinical features of genetic Parkinson’s disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson’s Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson’s study, 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1799 had late onset Parkinson’s disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson’s disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson’s disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

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