Journal
NEUROLOGY
Volume 78, Issue 22, Pages 1714-1720Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e3182556c05
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Funding
- NCI Cancer Center [P30 CA91842]
- ICTS/CTSA from the National Center for Research Resources (NCRR), a component of the NIH [UL1RR024992]
- NIH Roadmap for Medical Research
- Washington University
- BJC Institute for Clinical and Translational Sciences
- Children's Discovery Institute
- NIH [NS055980, NS069669, NS075094, GM47434, HD40182, U54NS065712-02]
- Neuroscience Blueprint Core Grant [NS057105]
- Hope Center for Neurological Disorders
- Muscular Dystrophy Association
- Charcot-Marie-Tooth Association
- Columbia University Motor Neuron Center
- Burroughs Wellcome Fund
- Genzyme
- Insmed
- Knopp
- Prosensa
- ISIS
- Sanofi
- MRC [G0601943] Funding Source: UKRI
- Medical Research Council [G0601943] Funding Source: researchfish
- Muscular Dystrophy UK [RA4/924, RA4/0924] Funding Source: researchfish
- Rosetrees Trust [M145] Funding Source: researchfish
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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 20) 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 (R) 2012;78:1714-1720
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