ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy
Hyung Jun Park MD
Department of Neurology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
Search for more papers by this authorYoung Bin Hong PhD
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Search for more papers by this authorYoung-Chul Choi MD, PhD
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
Search for more papers by this authorJinho Lee MD
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Search for more papers by this authorEun Ja Kim MD
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Search for more papers by this authorJi-Su Lee
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Search for more papers by this authorWon Min Mo MS
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Search for more papers by this authorSoo Mi Ki MS
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Search for more papers by this authorHyo In Kim
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Search for more papers by this authorHye Jin Kim
Department of Biological Science, Kongju National University, Gongju, South Korea
Search for more papers by this authorYoung Se Hyun PhD
Department of Biological Science, Kongju National University, Gongju, South Korea
Search for more papers by this authorHyun Dae Hong
Department of Biological Science, Kongju National University, Gongju, South Korea
Search for more papers by this authorKisoo Nam
Department of Chemistry, New York University, New York, NY
Search for more papers by this authorSung Chul Jung MD, PhD
Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, South Korea
Search for more papers by this authorSang-Beom Kim MD, PhD
Department of Neurology, Kyung Hee University College of Medicine, Kangdong Hospital, Seoul, South Korea
Search for more papers by this authorSe Hoon Kim MD, PhD
Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
Search for more papers by this authorDeok-Ho Kim PhD
Department of Bioengineering, University of Washington, Seattle, WA
Search for more papers by this authorKi-Wook Oh MD
Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea
Search for more papers by this authorSeung Hyun Kim MD, PhD
Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea
Search for more papers by this authorJeong Hyun Yoo MD, PhD
Department of Radiology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea
Search for more papers by this authorCorresponding Author
Ji Eun Lee PhD
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
Address correspondence to Dr Byung-Ok Choi, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]; Dr Ki Wha Chung, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 32588, Korea. E-mail: [email protected]; Dr Ji Eun Lee, Samsung Advanced Institute for Health Science & Tech., Samsung Genome Institute (SGI), Samsung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Ki Wha Chung PhD
Department of Biological Science, Kongju National University, Gongju, South Korea
Address correspondence to Dr Byung-Ok Choi, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]; Dr Ki Wha Chung, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 32588, Korea. E-mail: [email protected]; Dr Ji Eun Lee, Samsung Advanced Institute for Health Science & Tech., Samsung Genome Institute (SGI), Samsung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Byung-Ok Choi MD, PhD
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Neuroscience Center, Samsung Medical Center, Seoul, South Korea
Address correspondence to Dr Byung-Ok Choi, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]; Dr Ki Wha Chung, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 32588, Korea. E-mail: [email protected]; Dr Ji Eun Lee, Samsung Advanced Institute for Health Science & Tech., Samsung Genome Institute (SGI), Samsung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]Search for more papers by this authorHyung Jun Park MD
Department of Neurology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
Search for more papers by this authorYoung Bin Hong PhD
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Search for more papers by this authorYoung-Chul Choi MD, PhD
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
Search for more papers by this authorJinho Lee MD
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Search for more papers by this authorEun Ja Kim MD
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Search for more papers by this authorJi-Su Lee
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Search for more papers by this authorWon Min Mo MS
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Search for more papers by this authorSoo Mi Ki MS
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Search for more papers by this authorHyo In Kim
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Search for more papers by this authorHye Jin Kim
Department of Biological Science, Kongju National University, Gongju, South Korea
Search for more papers by this authorYoung Se Hyun PhD
Department of Biological Science, Kongju National University, Gongju, South Korea
Search for more papers by this authorHyun Dae Hong
Department of Biological Science, Kongju National University, Gongju, South Korea
Search for more papers by this authorKisoo Nam
Department of Chemistry, New York University, New York, NY
Search for more papers by this authorSung Chul Jung MD, PhD
Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, South Korea
Search for more papers by this authorSang-Beom Kim MD, PhD
Department of Neurology, Kyung Hee University College of Medicine, Kangdong Hospital, Seoul, South Korea
Search for more papers by this authorSe Hoon Kim MD, PhD
Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
Search for more papers by this authorDeok-Ho Kim PhD
Department of Bioengineering, University of Washington, Seattle, WA
Search for more papers by this authorKi-Wook Oh MD
Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea
Search for more papers by this authorSeung Hyun Kim MD, PhD
Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea
Search for more papers by this authorJeong Hyun Yoo MD, PhD
Department of Radiology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea
Search for more papers by this authorCorresponding Author
Ji Eun Lee PhD
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
Address correspondence to Dr Byung-Ok Choi, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]; Dr Ki Wha Chung, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 32588, Korea. E-mail: [email protected]; Dr Ji Eun Lee, Samsung Advanced Institute for Health Science & Tech., Samsung Genome Institute (SGI), Samsung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Ki Wha Chung PhD
Department of Biological Science, Kongju National University, Gongju, South Korea
Address correspondence to Dr Byung-Ok Choi, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]; Dr Ki Wha Chung, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 32588, Korea. E-mail: [email protected]; Dr Ji Eun Lee, Samsung Advanced Institute for Health Science & Tech., Samsung Genome Institute (SGI), Samsung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Byung-Ok Choi MD, PhD
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
Neuroscience Center, Samsung Medical Center, Seoul, South Korea
Address correspondence to Dr Byung-Ok Choi, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]; Dr Ki Wha Chung, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 32588, Korea. E-mail: [email protected]; Dr Ji Eun Lee, Samsung Advanced Institute for Health Science & Tech., Samsung Genome Institute (SGI), Samsung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]Search for more papers by this authorAbstract
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. Ann Neurol 2016;79:231–243
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