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

Neurology. 2012 May 29;78(22):1714-20. doi: 10.1212/WNL.0b013e3182556c05. Epub 2012 Mar 28.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Chromosomes, Human, Pair 14* / genetics
  • Cytoplasmic Dyneins / genetics*
  • Cytoplasmic Dyneins / metabolism
  • Female
  • Genes, Dominant* / genetics
  • Humans
  • Infant
  • Lower Extremity*
  • Male
  • Mutation, Missense*
  • Polymorphism, Single Nucleotide*
  • Sequence Analysis, DNA / methods
  • Spinal Muscular Atrophies of Childhood / genetics*


  • DYNC1H1 protein, human
  • Cytoplasmic Dyneins