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

M. B. Harms, K. M. Ori-McKenney, M. Scoto, E. P. Tuck, S. Bell, D. Ma, S. Masi, P. Allred, M. Al-Lozi, M. M. Reilly, L. J. Miller, A. Jani-Acsadi, A. Pestronk, M. E. Shy, F. Muntoni, R. B. Vallee, R. H. Baloh

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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 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.

Original languageEnglish
Pages (from-to)1714-1720
Number of pages7
Issue number22
StatePublished - May 29 2012

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    Harms, M. B., Ori-McKenney, K. M., Scoto, M., Tuck, E. P., Bell, S., Ma, D., Masi, S., Allred, P., Al-Lozi, M., Reilly, M. M., Miller, L. J., Jani-Acsadi, A., Pestronk, A., Shy, M. E., Muntoni, F., Vallee, R. B., & Baloh, R. H. (2012). Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology, 78(22), 1714-1720.