ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy

Hyung Jun Park, Young Bin Hong, Youngchul Choi, Jinho Lee, Eun Ja Kim, Ji Su Lee, Won Min Mo, Soo Mi Ki, Hyo In Kim, Hye Jin Kim, Young Se Hyun, Hyun Dae Hong, Kisoo Nam, Sung Chul Jung, Sang Beom Kim, SeHoon Kim, Deok Ho Kim, Ki Wook Oh, Seung Hyun Kim, Jeong Hyun YooJi Eun Lee, Ki Wha Chung, Byung Ok Choi

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)231-243
Number of pages13
JournalAnnals of Neurology
Volume79
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1

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Distal Myopathies
Mutation
Exome
Myoblasts
Muscle Weakness
Zebrafish
Muscles
Adenylosuccinate Synthase
Facial Muscles
Gene Knockdown Techniques
Birefringence
Molecular Pathology
Muscle Proteins
Muscular Diseases
Myosins
Creatine Kinase
Vacuoles
Phenotype
Serum

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Park, H. J., Hong, Y. B., Choi, Y., Lee, J., Kim, E. J., Lee, J. S., ... Choi, B. O. (2016). ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy. Annals of Neurology, 79(2), 231-243. https://doi.org/10.1002/ana.24550
Park, Hyung Jun ; Hong, Young Bin ; Choi, Youngchul ; Lee, Jinho ; Kim, Eun Ja ; Lee, Ji Su ; Mo, Won Min ; Ki, Soo Mi ; Kim, Hyo In ; Kim, Hye Jin ; Hyun, Young Se ; Hong, Hyun Dae ; Nam, Kisoo ; Jung, Sung Chul ; Kim, Sang Beom ; Kim, SeHoon ; Kim, Deok Ho ; Oh, Ki Wook ; Kim, Seung Hyun ; Yoo, Jeong Hyun ; Lee, Ji Eun ; Chung, Ki Wha ; Choi, Byung Ok. / ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy. In: Annals of Neurology. 2016 ; Vol. 79, No. 2. pp. 231-243.
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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.",
author = "Park, {Hyung Jun} and Hong, {Young Bin} and Youngchul Choi and Jinho Lee and Kim, {Eun Ja} and Lee, {Ji Su} and Mo, {Won Min} and Ki, {Soo Mi} and Kim, {Hyo In} and Kim, {Hye Jin} and Hyun, {Young Se} and Hong, {Hyun Dae} and Kisoo Nam and Jung, {Sung Chul} and Kim, {Sang Beom} and SeHoon Kim and Kim, {Deok Ho} and Oh, {Ki Wook} and Kim, {Seung Hyun} and Yoo, {Jeong Hyun} and Lee, {Ji Eun} and Chung, {Ki Wha} and Choi, {Byung Ok}",
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Park, HJ, Hong, YB, Choi, Y, Lee, J, Kim, EJ, Lee, JS, Mo, WM, Ki, SM, Kim, HI, Kim, HJ, Hyun, YS, Hong, HD, Nam, K, Jung, SC, Kim, SB, Kim, S, Kim, DH, Oh, KW, Kim, SH, Yoo, JH, Lee, JE, Chung, KW & Choi, BO 2016, 'ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy', Annals of Neurology, vol. 79, no. 2, pp. 231-243. https://doi.org/10.1002/ana.24550

ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy. / Park, Hyung Jun; Hong, Young Bin; Choi, Youngchul; Lee, Jinho; Kim, Eun Ja; Lee, Ji Su; Mo, Won Min; Ki, Soo Mi; Kim, Hyo In; Kim, Hye Jin; Hyun, Young Se; Hong, Hyun Dae; Nam, Kisoo; Jung, Sung Chul; Kim, Sang Beom; Kim, SeHoon; Kim, Deok Ho; Oh, Ki Wook; Kim, Seung Hyun; Yoo, Jeong Hyun; Lee, Ji Eun; Chung, Ki Wha; Choi, Byung Ok.

In: Annals of Neurology, Vol. 79, No. 2, 01.02.2016, p. 231-243.

Research output: Contribution to journalArticle

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T1 - ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy

AU - Park, Hyung Jun

AU - Hong, Young Bin

AU - Choi, Youngchul

AU - Lee, Jinho

AU - Kim, Eun Ja

AU - Lee, Ji Su

AU - Mo, Won Min

AU - Ki, Soo Mi

AU - Kim, Hyo In

AU - Kim, Hye Jin

AU - Hyun, Young Se

AU - Hong, Hyun Dae

AU - Nam, Kisoo

AU - Jung, Sung Chul

AU - Kim, Sang Beom

AU - Kim, SeHoon

AU - Kim, Deok Ho

AU - Oh, Ki Wook

AU - Kim, Seung Hyun

AU - Yoo, Jeong Hyun

AU - Lee, Ji Eun

AU - Chung, Ki Wha

AU - Choi, Byung Ok

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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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