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ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy

 Hyung Jun Park  ;  Young Bin Hong  ;  Young-Chul Choi  ;  Jinho Lee  ;  Eun Ja Kim  ;  Ji-Su Lee  ;  Won Min Mo  ;  Soo Mi Ki  ;  Hyo In Kim  ;  Hye Jin Kim  ;  Young Se Hyun  ;  Hyun Dae Hong  ;  Kisoo Nam  ;  Sung Chul Jung  ;  Sang-Beom Kim  ;  Se Hoon Kim  ;  Deok-Ho Kim  ;  Ki-Wook Oh  ;  Seung Hyun Kim  ;  Jeong Hyun Yoo  ;  Ji Eun Lee  ;  Ki Wha Chung  ;  Byung-Ok Choi 
 ANNALS OF NEUROLOGY, Vol.79(2) : 231-243, 2016 
Journal Title
Issue Date
Adenylosuccinate Synthase/genetics* ; Adult ; Age of Onset ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Distal Myopathies/enzymology ; Distal Myopathies/genetics* ; Distal Myopathies/physiopathology ; Female ; Humans ; Male ; Mice ; Mutation ; Pedigree ; Phenotype ; Republic of Korea ; Young Adult ; Zebrafish ; Zebrafish Proteins
OBJECTIVE: Distal 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. METHODS: Four 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. RESULTS: Patients 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. INTERPRETATION: We 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.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Choi, Young Chul(최영철) ORCID logo https://orcid.org/0000-0001-5525-6861
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