C: Genetic modifiers最新文献

C03 FAN1 coding variants identified in individuals with Huntington’s disease implicate its nuclease activity and dna binding in age at onset 在亨廷顿舞蹈病个体中发现的C03 FAN1编码变异与发病年龄的核酸酶活性和dna结合有关

C: Genetic modifiers Pub Date : 2022-09-01 DOI: 10.1136/jnnp-2022-ehdn.47

Caroline S. Binda, Branduff McAllister, G. Menzies, Gareth Edwards, James Davies, L. Jones, Thomas H. Massey

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C06 The role of FAN1 in HTT cag repeat instability and age at onset in the R6/1 mouse model of Huntington’s disease 在R6/1亨廷顿病小鼠模型中，FAN1在HTT cag重复不稳定性和发病年龄中的作用

C: Genetic modifiers Pub Date : 2022-09-01 DOI: 10.1136/jnnp-2022-ehdn.50

K. Fears, Caroline S. Binda, Elin Miles, Thomas H. Massey, L. Jones

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C08 Knockout of mismatch repair genes MLH1 and MSH3 ablates expansion of the CAG repeat in a human iPSC model of Huntington’s disease 在亨廷顿病人类iPSC模型中，敲除错配修复基因MLH1和MSH3可减少CAG重复序列的扩增

C: Genetic modifiers Pub Date : 2022-09-01 DOI: 10.1136/jnnp-2022-ehdn.52

Joseph Stone, Thomas H. Massey, Nicholas Allen, L. Jones

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C10 Haplotype structure analysis of Indian Huntington’s disease patients at HTT gene locus 印度亨廷顿舞蹈病HTT基因位点C10单倍型结构分析

C: Genetic modifiers Pub Date : 2022-09-01 DOI: 10.1136/jnnp-2022-ehdn.54

Sowmya Devatha Venkatesh, M. Varghese, Ravikant Yadav, S. Jain, M. Purushottam

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C12 HTT repeat instability in family trios in the 100,000 genomes project 在100,000个基因组计划中，三家族的C12 HTT重复不稳定性

C: Genetic modifiers Pub Date : 2022-09-01 DOI: 10.1136/jnnp-2022-ehdn.56

Davina J. Hensman Moss, Anupriya Dalmia, Valentina Galassi Deforie, K. Ibáñez, S. Tabrizi, N. Lahiri, H. Houlden, P. Holmans, L. Jones, A. Tucci

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C11 Identifying loss-of-interruptions (LOI) in huntington disease families of Italian origin C11鉴定意大利血统亨廷顿病家族的中断缺失(LOI)

C: Genetic modifiers Pub Date : 2022-09-01 DOI: 10.1136/jnnp-2022-ehdn.55

Alessia Squitieri, Ludovica C Busi, Marco Di Marsico, F. Perrone, T. Mazza, R. Aiese Cigliano, F. Squitieri

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C07 A CRISPRI platform to assess the role of HD risk modifiers in CAG repeat expansion in iPSC derived striatal neurons C07利用CRISPRI平台评估HD风险修饰因子在诱导多能干细胞衍生纹状体神经元CAG重复扩增中的作用

C: Genetic modifiers Pub Date : 2022-09-01 DOI: 10.1136/jnnp-2022-ehdn.51

Ross Ferguson, M. Flower, S. Tabrizi

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C05 The role of FAN1 nuclease activity and mlh1 binding in stabilisation of the cag repeat in HD-IPSC derived models C05在HD-IPSC衍生模型中，FAN1核酸酶活性和mlh1结合在cag重复序列稳定中的作用

C: Genetic modifiers Pub Date : 2022-09-01 DOI: 10.1136/jnnp-2022-ehdn.49

Jasmine Donaldson, Joseph Hamilton, Jessica F. Olive, R. Goold, S. Tabrizi

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Huntingtin gene CAG repeat size in patients with Lynch syndrome Lynch综合征患者亨廷顿基因CAG重复序列大小

C: Genetic modifiers Pub Date : 2022-05-29 DOI: 10.1101/2022.05.28.22275723

S. Gebre-Medhin, K. Dalene Skarping, A. Petersen

{"title":"Huntingtin gene CAG repeat size in patients with Lynch syndrome","authors":"S. Gebre-Medhin, K. Dalene Skarping, A. Petersen","doi":"10.1101/2022.05.28.22275723","DOIUrl":"https://doi.org/10.1101/2022.05.28.22275723","url":null,"abstract":"Patients with Lynch syndrome (LS) are prone to cancer due to heterozygous germline pathogenic variants in genes encoding DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. LS cancer cells exhibit deficient DNA mismatch repair and microsatellite instability due somatic inactivation of the second copy of the affected gene. To study microsatellite characteristics in non-neoplastic cells in LS we determined CAG repeat size in the huntingtin gene (HTT) microsatellite in lymphocyte DNA from LS patients with germline pathogenic variants in MLH1 (n = 11), MSH2 (n = 9), MSH6 (n = 7) and non-LS controls (n=19). Mean repeat size in LS was 19,55 CAG (MLH1), 19,39 CAG (MSH2), 18.07 CAG (MSH6), respectively compared to 18,42 CAG in controls. Standard deviation for CAG repeat size in LS was 4,183 CAG (MLH1), 5,089 CAG (MSH2), 3,075 CAG (MSH6), respectively, compared to 3,342 CAG in controls. Peak CAG repeat size in LS was 32 CAG (MLH1), 32 CAG (MSH2), 24 CAG (MSH6), respectively compared to 27 CAG in controls. Collectively, our data indicate that HTT CAG repeat size tends to be larger and more variable in individuals with LS caused by pathogenic variants in MLH1 and MSH2.","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"170 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116418559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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C04 Protein coding tandem repeat in TCERG1 modifies huntington’s disease onset TCERG1中的C04蛋白编码串联重复修饰亨廷顿病的发病

C: Genetic modifiers Pub Date : 2021-09-01 DOI: 10.1136/jnnp-2021-ehdn.28

S. Lobanov, Branduff McAllister, M. McDade-Kumar, Jong-Min Lee, M. MacDonald, J. Gusella, M. Ryten, N. Williams, P. Holmans, Thomas H. Massey, L. Jones

{"title":"C04 Protein coding tandem repeat in TCERG1 modifies huntington’s disease onset","authors":"S. Lobanov, Branduff McAllister, M. McDade-Kumar, Jong-Min Lee, M. MacDonald, J. Gusella, M. Ryten, N. Williams, P. Holmans, Thomas H. Massey, L. Jones","doi":"10.1136/jnnp-2021-ehdn.28","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.28","url":null,"abstract":"Background The length of the HTT CAG repeat explains around 60% of the variance in Huntington’s disease (HD) age at onset. Recently, genome-wide association studies (GWAS) of HD age at onset have identified multiple single nucleotide variants (SNVs) that influence onset, including an intronic SNV, rs79727797, in TCERG1 (p=3.76E-10). Aims Since the SNV does not modify the protein or appear to change gene expression, we tested whether the GWAS signal is due to genetic variation not present in the GWAS. Methods/Techniques We developed a novel method for calling perfect and imperfect short tandem repeats from whole exome sequencing (WES) data, and applied it to 610 WES samples from HD individuals with age at onset or cognitive test data discrepant from those predicted by their HTT CAG length. We identified an exonic (CAGGCC)n short tandem repeat in TCERG1 previously reported to be associated with altered HD age at onset. The reference allele is (CAGGCC)6. We identified 5 length alleles with 3 to 8 hexamer repeats. Results/Outcome Reduced repeat length is significantly associated with later HD age-at-onset (sum of repeat from both TCERG1 repeat alleles: p=6.51E-9). The (CAGGCC)3 allele (frequency 4.1%) is in linkage disequilibrium (r2=0.98) with the minor allele at rs79727797, associated with later onset in the GWAS. Conditioning the association of rs79727797 on TCERG1 (CAGGCC)n length reduces its significance from p=2.4E-6 to p=0.96, while STR length is still significantly associated with HD age at onset after conditioning on rs79727797 (p=3.9E-4). This indicates that the repeat, rather than rs79727797, is responsible for the association at this locus. Conclusion The GWAS signal in TCERG1 is attributable to a short tandem repeat, rather than SNVs. Further biological study of the mechanism by which it alters HD age at onset is warranted.","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127068320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0