Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development

Chiara Fiorillo, Francesca Moro, Julie Yi, Sarah Weil, Giacomo Brisca, Guja Astrea, Mariasavina Severino, Alessandro Romano, Roberta Battini, Andrea Rossi, Carlo Minetti, Claudio Bruno, Filippo M. Santorelli, Richard Vallee

Research output: Contribution to journalArticlepeer-review


DYNC1H1 encodes the heavy chain of cytoplasmic dynein 1, a motor protein complex implicated in retrograde axonal transport, neuronal migration, and other intracellular motility functions. Mutations in DYNC1H1 have been described in autosomal-dominant Charcot-Marie-Tooth type 2 and in families with distal spinal muscular atrophy (SMA) predominantly affecting the legs (SMA-LED). Recently, defects of cytoplasmic dynein 1 were also associated with a form of mental retardation and neuronal migration disorders. Here, we describe two unrelated patients presenting a combined phenotype of congenital motor neuron disease associated with focal areas of cortical malformation. In each patient, we identified a novel de novo mutation in DYNC1H1: c.3581A>G (p.Gln1194Arg) in one case and c.9142G>A (p.Glu3048Lys) in the other. The mutations lie in different domains of the dynein heavy chain, and are deleterious to protein function as indicated by assays for Golgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC1H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration, and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems.

Original languageEnglish
Pages (from-to)298-302
Number of pages5
JournalHuman Mutation
Issue number3
Publication statusPublished - 2014


  • Abnormal cortical development
  • Distal SMA
  • DYNC1H1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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