期刊
HUMAN MUTATION
卷 41, 期 9, 页码 1540-1554出版社
WILEY
DOI: 10.1002/humu.24036
关键词
arginine and tryptophan (R; W) stacking; dysferlin; inner DysF domain; limb-girdle muscular dystrophy type 2B; Miyoshi muscular dystrophy; next-generation sequencing
资金
- Japan Society for the Promotion of Science [17K16107, 18K15437, 26670436, 18K19505, 15H05667, 18K07519, 16H05318]
- Japan Agency for Medical Research and Development (AMED) [15ek0109067h0002, 18dk0310086, JP19ek0109259]
- National Center of Neurology and Psychiatry of Japan [29-3, 29-4]
- Ministry of Health, Labour and Welfare of Japan [H26-nanchitou(nan)-ippan-079, H29nanchitou(nan)-ippan-030, H30-nanchitou (nan)-ippan-005]
- Grants-in-Aid for Scientific Research [15H05667, 18K07519, 18K19505, 18K15437, 17K16107, 26670436, 16H05318] Funding Source: KAKEN
Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performedDYSFgene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb-girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.
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