Hyung Jun Park1,2, Young Bin Hong3, Young-Chul Choi2, Jinho Lee3, Eun Ja Kim3, Ji-Su Lee4, Won Min Mo3, Soo Mi Ki4, Hyo In Kim4, Hye Jin Kim5, Young Se Hyun5, Hyun Dae Hong5, Kisoo Nam6, Sung Chul Jung7, Sang-Beom Kim8, Se Hoon Kim9, Deok-Ho Kim10, Ki-Wook Oh11, Seung Hyun Kim11, Jeong Hyun Yoo12, Ji Eun Lee4,13, Ki Wha Chung5, Byung-Ok Choi3,4,14. 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.
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.
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.
Authors: SooJin Kwon; Soo Mi Ki; Sang Eon Park; Min-Jeong Kim; Brian Hyung; Na Kyung Lee; Sangmi Shim; Byung-Ok Choi; Duk L Na; Ji Eun Lee; Jong Wook Chang Journal: Mol Ther Date: 2016-06-23 Impact factor: 11.454
Authors: Marco Savarese; Jaakko Sarparanta; Anna Vihola; Per Harald Jonson; Mridul Johari; Salla Rusanen; Peter Hackman; Bjarne Udd Journal: Acta Myol Date: 2020-12-01
Authors: Christopher Grunseich; Nathan Sarkar; Joyce Lu; Mallory Owen; Alice Schindler; Peter A Calabresi; Charlotte J Sumner; Ricardo H Roda; Vinay Chaudhry; Thomas E Lloyd; Thomas O Crawford; S H Subramony; Shin J Oh; Perry Richardson; Kurenai Tanji; Justin Y Kwan; Kenneth H Fischbeck; Ami Mankodi Journal: J Neurol Neurosurg Psychiatry Date: 2021-06-08 Impact factor: 10.154