title: Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.
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.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disease,Washington University School of Medicine, St. Louis, MO, USA. robert.baloh@csmc.edu
authors.forename: M B
authors.initials: MB
authors.lastname: Harms
authors.forename: K M
authors.initials: KM
authors.lastname: Ori-McKenney
authors.forename: M
authors.initials: M
authors.lastname: Scoto
authors.forename: E P
authors.initials: EP
authors.lastname: Tuck
authors.forename: S
authors.initials: S
authors.lastname: Bell
authors.forename: D
authors.initials: D
authors.lastname: Ma
authors.forename: S
authors.initials: S
authors.lastname: Masi
authors.forename: P
authors.initials: P
authors.lastname: Allred
authors.forename: M
authors.initials: M
authors.lastname: Al-Lozi
authors.forename: M M
authors.initials: MM
authors.lastname: Reilly
authors.forename: L J
authors.initials: LJ
authors.lastname: Miller
authors.forename: A
authors.initials: A
authors.lastname: Jani-Acsadi
authors.forename: A
authors.initials: A
authors.lastname: Pestronk
authors.forename: M E
authors.initials: ME
authors.lastname: Shy
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.forename: R B
authors.initials: RB
authors.lastname: Vallee
authors.forename: R H
authors.initials: RH
authors.lastname: Baloh
mesh_terms: D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D056445:Cytoplasmic Dyneins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D007223:Infant; D035002:Lower Extremity; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics*
chemical_list: C511240:DYNC1H1 protein, human; D056445:Cytoplasmic Dyneins