2. Academic Validation
  3. ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy

ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy

  • Ann Neurol. 2016 Feb;79(2):231-43. doi: 10.1002/ana.24550.
Hyung Jun Park 1 2,  Young Bin Hong 3,  Young-Chul Choi 2,  Jinho Lee 3,  Eun Ja Kim 3,  Ji-Su Lee 4,  Won Min Mo 3,  Soo Mi Ki 4,  Hyo In Kim 4,  Hye Jin Kim 5,  Young Se Hyun 5,  Hyun Dae Hong 5,  Kisoo Nam 6,  Sung Chul Jung 7,  Sang-Beom Kim 8,  Se Hoon Kim 9,  Deok-Ho Kim 10,  Ki-Wook Oh 11,  Seung Hyun Kim 11,  Jeong Hyun Yoo 12,  Ji Eun Lee 4 13,  Ki Wha Chung 5,  Byung-Ok Choi 3 4 14
Affiliations

Affiliations

  • 1 Department of Neurology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea.
  • 2 Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.
  • 3 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
  • 4 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
  • 5 Department of Biological Science, Kongju National University, Gongju, South Korea.
  • 6 Department of Chemistry, New York University, New York, NY.
  • 7 Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, South Korea.
  • 8 Department of Neurology, Kyung Hee University College of Medicine, Kangdong Hospital, Seoul, South Korea.
  • 9 Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea.
  • 10 Department of Bioengineering, University of Washington, Seattle, WA.
  • 11 Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea.
  • 12 Department of Radiology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea.
  • 13 Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
  • 14 Neuroscience Center, Samsung Medical Center, Seoul, South Korea.
PMID: 26506222 DOI: 10.1002/ana.24550
Abstract

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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