Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy
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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.
GLOSSARY
- CMT=
- Charcot-Marie-Tooth;
- gDNA=
- genomic DNA;
- indels=
- insertions/deletions;
- SDS-PAGE=
- sodium dodecyl sulfate polyacrylamide gel electrophoresis;
- SMA=
- spinal muscular atrophy;
- SMA-LED=
- spinal muscular atrophy with lower extremity predominance;
- SNP=
- single nucleotide polymorphism.
Footnotes
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Study funding: Supported by the BJC Institute for Clinical and Translational Sciences, the Children's Discovery Institute, NIH grants NS055980 and NS069669 (R.H.B.), NS075094 (M.B.H.), GM47434 and HD40182 (R.B.V.), U54NS065712–02 (M.E.S.), the Neuroscience Blueprint Core Grant NS057105 to Washington University, the Hope Center for Neurological Disorders, the Muscular Dystrophy Association (R.H.B., M.E.S.), the Charcot-Marie-Tooth Association (M.E.S.), and the Columbia University Motor Neuron Center (R.B.V.). R.H.B. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. There were no industry sponsors of this study.
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Editorial, page 1706.
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Supplemental data at www.neurology.org
- Received August 30, 2011.
- Accepted October 18, 2011.
- Copyright © 2012 by AAN Enterprises, Inc.
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