Hyung Jun Park MD^1,3, Young Bin Hong PhD², Young-Chul Choi MD, PhD³, Jinho Lee MD², Eun Ja Kim MD², Ji-Su Lee⁴, Won Min Mo MS², Soo Mi Ki MS⁴, Hyo In Kim⁴, Hye Jin Kim⁵, Young Se Hyun PhD⁵, Hyun Dae Hong⁵, Kisoo Nam⁶, Sung Chul Jung MD, PhD⁷, Sang-Beom Kim MD, PhD⁸, Se Hoon Kim MD, PhD⁹, Deok-Ho Kim PhD¹⁰, Ki-Wook Oh MD¹¹, Seung Hyun Kim MD, PhD^11, Jeong Hyun Yoo MD, PhD¹⁴, Ji Eun Lee PhD^4,12,*, Ki Wha Chung PhD^5,* and Byung-Ok Choi MD, PhD^2,4,13

¹ Department of Neurology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul

² Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul

³ Department of Neurology, Yonsei University College of Medicine, Seoul

⁴ Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science & Tech., Sungkyunkwan University, Seoul

⁵ Department of Biological Science, Kongju National University, Gongju

⁶ Department of Chemistry, New York University, New York, NY, USA

⁷ Department of Biochemistry, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul

⁸ Department of Neurology, Kyung Hee University College of Medicine, Kangdong Hospital, Seoul

⁹ Department of Pathology, Yonsei University College of Medicine, Seoul

¹⁰ Department of Bioengineering, University of Washington, WA, USA

¹¹ Department of Neurology, College of Medicine, Hanyang University, Seoul

¹² Samsung Genome Institute, Samsung Medical Center, Seoul

¹³ Neuroscience center, Samsung Medical Center, Seoul

¹⁴ Department of Radiology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul

^*Address co-correspondences to Dr Byung-Ok Choi, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 135-710, Korea. Dr Ki Wha Chung, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 314-701, Korea. 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 135-710, Korea. 

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 two 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 which included distal dominant weakness, facial muscle weakness, rimmed vacuole, 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 knock-down 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 knock-downed 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. This article is protected by copyright. All rights reserved.

Keywords : distal myopathy; exome sequencing; ADSSL1