ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy.
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.


CONCLUSIONS
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.
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.
Hyung Jun
HJ
Park
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Young Bin
YB
Hong
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.
Young-Chul
YC
Choi
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Jinho
J
Lee
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Eun Ja
EJ
Kim
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
Ji-Su
JS
Lee
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Won Min
WM
Mo
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
Soo Mi
SM
Ki
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
Hyo In
HI
Kim
Department of Biological Science, Kongju National University, Gongju, South Korea.
Hye Jin
HJ
Kim
Department of Biological Science, Kongju National University, Gongju, South Korea.
Young Se
YS
Hyun
Department of Biological Science, Kongju National University, Gongju, South Korea.
Hyun Dae
HD
Hong
Department of Chemistry, New York University, New York, NY.
Kisoo
K
Nam
Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, South Korea.
Sung Chul
SC
Jung
Department of Neurology, Kyung Hee University College of Medicine, Kangdong Hospital, Seoul, South Korea.
Sang-Beom
SB
Kim
Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea.
Se Hoon
SH
Kim
Department of Bioengineering, University of Washington, Seattle, WA.
Deok-Ho
DH
Kim
Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea.
Ki-Wook
KW
Oh
Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea.
Seung Hyun
SH
Kim
Department of Radiology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea.
Jeong Hyun
JH
Yoo
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.
Ji Eun
JE
Lee
Department of Biological Science, Kongju National University, Gongju, South Korea.
Ki Wha
KW
Chung
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.
Byung-Ok
BO
Choi
D000265:Adenylosuccinate Synthase / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D049310:Distal Myopathies / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D056910:Republic of Korea; D055815:Young Adult; D015027:Zebrafish; D029961:Zebrafish Proteins
D029961:Zebrafish Proteins; C503206:ADSS1 protein, human; D000265:Adenylosuccinate Synthase