Mutations in the tail domain of DYNC1H1 cause dominant spinal: muscular atrophy

M. B HARMS; K. M ORI-MCKENNEY; L. J MILLER; A JANI-ACSADI; A PESTRONK; M. E SHY; F MUNTONI; R. B VALLEE; R. H BALOH; M SCOTO; E. P TUCK; S BELL; D MA; S MASI; P ALLRED; M AL-LOZI; M. M REILLY

doi:10.1212/WNL.0b013e3182556c05

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Mutations in the tail domain of DYNC1H1 cause dominant spinal: muscular atrophy

Journal article

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Mutations in the tail domain of DYNC1H1 cause dominant spinal: muscular atrophy

M. B HARMS, K. M ORI-MCKENNEY, L. J MILLER, A JANI-ACSADI, A PESTRONK, M. E SHY, F MUNTONI, R. B VALLEE, R. H BALOH, M SCOTO, …

Neurology, Vol.78(22), pp.1714-1720

2012

DOI: 10.1212/WNL.0b013e3182556c05

PMCID: PMC3359582

PMID: 22459677

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Abstract

Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600). Methods: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed. Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state—a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function. Conclusions: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance.

Neurology

Biological and medical sciences

Medical sciences

Diseases of striated muscles. Neuromuscular diseases

Details

Title: Subtitle: Mutations in the tail domain of DYNC1H1 cause dominant spinal: muscular atrophy
Creators: M. B HARMS - Department of Neurology (M.B.H., E.P.T., S.B., D.M., S.M., P.A., M.A.-L., A.P., R.H.B.), Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO, United States
K. M ORI-MCKENNEY - Department of Pathology and Cell Biology (K.M.O.-M., R.B.V.), Columbia University, New York, NY, United States
L. J MILLER - Department of Neurology (L.J.M., A.J.-A., M.E.S.), Wayne State University, Detroit, MI, United States
A JANI-ACSADI - Department of Neurology (L.J.M., A.J.-A., M.E.S.), Wayne State University, Detroit, MI, United States
A PESTRONK - Department of Neurology (M.B.H., E.P.T., S.B., D.M., S.M., P.A., M.A.-L., A.P., R.H.B.), Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO, United States
M. E SHY - Department of Neurology (L.J.M., A.J.-A., M.E.S.), Wayne State University, Detroit, MI, United States
F MUNTONI - Dubowitz Neuromuscular Centre (M.S., F.M.), UCL Institute of Child Health, London, United Kingdom
R. B VALLEE - Department of Pathology and Cell Biology (K.M.O.-M., R.B.V.), Columbia University, New York, NY, United States
R. H BALOH - Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
M SCOTO - Dubowitz Neuromuscular Centre (M.S., F.M.), UCL Institute of Child Health, London, United Kingdom
E. P TUCK - Department of Neurology (M.B.H., E.P.T., S.B., D.M., S.M., P.A., M.A.-L., A.P., R.H.B.), Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO, United States
S BELL - Department of Neurology (M.B.H., E.P.T., S.B., D.M., S.M., P.A., M.A.-L., A.P., R.H.B.), Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO, United States
D MA - Department of Neurology (M.B.H., E.P.T., S.B., D.M., S.M., P.A., M.A.-L., A.P., R.H.B.), Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO, United States
S MASI - Department of Neurology (M.B.H., E.P.T., S.B., D.M., S.M., P.A., M.A.-L., A.P., R.H.B.), Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO, United States
P ALLRED - Department of Neurology (M.B.H., E.P.T., S.B., D.M., S.M., P.A., M.A.-L., A.P., R.H.B.), Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO, United States
M AL-LOZI - Department of Neurology (M.B.H., E.P.T., S.B., D.M., S.M., P.A., M.A.-L., A.P., R.H.B.), Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO, United States
M. M REILLY - MRC Centre for Neuromuscular Diseases (M.M.R.), UCL Institute of Neurology, London, United Kingdom
Resource Type: Journal article
Publication Details: Neurology, Vol.78(22), pp.1714-1720
DOI: 10.1212/WNL.0b013e3182556c05
PMID: 22459677
PMCID: PMC3359582
NLM abbreviation: Neurology
ISSN: 0028-3878
eISSN: 1526-632X
Publisher: Lippincott Williams & Wilkins; Hagerstown, MD
Language: English
Date published: 2012
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984020611802771

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