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ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy

Title
ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy
Authors
Park, Hyung JunHong, Young BinChoi, Young-ChulLee, JinhoKim, Eun JaLee, Ji-SuMo, Won MinKi, Soo MiKim, Hyo InKim, Hye JinHyun, Young SeHong, Hyun DaeNam, KisooJung, Sung ChulKim, Sang-BeomKim, Se HoonKim, Deok-HoOh, Ki-WookKim, Seung HyunYoo, Jeong HyunLee, Ji EunChung, Ki WhaChoi, Byung-Ok
Ewha Authors
유정현정성철박형준
SCOPUS Author ID
유정현scopus; 정성철scopus; 박형준scopusscopus
Issue Date
2016
Journal Title
ANNALS OF NEUROLOGY
ISSN
0364-5134JCR Link1531-8249JCR Link
Citation
vol. 79, no. 2, pp. 231 - 243
Publisher
WILEY-BLACKWELL
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
ObjectiveDistal myopathy is a heterogeneous group of muscle diseases characterized by predominant distal muscle weakness. A study was done to identify the underlying cause of autosomal recessive adolescent onset distal myopathy. MethodsFour patients from 2 unrelated Korean families were evaluated. To isolate the genetic cause, exome sequencing was performed. In vitro and in vivo assays using myoblast cells and zebrafish models were performed to examine the ADSSL1 mutation causing myopathy pathogenesis. ResultsPatients had an adolescent onset distal myopathy phenotype that included distal dominant weakness, facial muscle weakness, rimmed vacuoles, and mild elevation of serum creatine kinase. Exome sequencing identified completely cosegregating compound heterozygous mutations (p.D304N and p.I350fs) in ADSSL1, which encodes a muscle-specific adenylosuccinate synthase in both families. None of the controls had both mutations, and the mutation sites were located in well-conserved regions. Both the D304N and I350fs mutations in ADSSL1 led to decreased enzymatic activity. The knockdown of the Adssl1 gene significantly inhibited the proliferation of mouse myoblast cells, and the addition of human wild-type ADSSL1 reversed the reduced viability. In an adssl1 knockdown zebrafish model, muscle fibers were severely disrupted, which was evaluated by myosin expression and birefringence. In these conditions, supplementing wild-type ADSSL1 protein reversed the muscle defect. InterpretationWe suggest that mutations in ADSSL1 are the novel genetic cause of the autosomal recessive adolescent onset distal myopathy. This study broadens the genetic and clinical spectrum of distal myopathy and will be useful for exact molecular diagnostics. Ann Neurol 2016;79:231-243
DOI
10.1002/ana.24550
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의학전문대학원 > 의학과 > Journal papers
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