Premium
Novel Dynein DYNC 1 H 1 Neck and Motor Domain Mutations Link Distal Spinal Muscular Atrophy and Abnormal Cortical Development
Author(s) -
Fiorillo Chiara,
Moro Francesca,
Yi Julie,
Weil Sarah,
Brisca Giacomo,
Astrea Guja,
Severino Mariasavina,
Romano Alessandro,
Battini Roberta,
Rossi Andrea,
Minetti Carlo,
Bruno Claudio,
Santorelli Filippo M.,
Vallee Richard
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22491
Subject(s) - spinal muscular atrophy , dynein , biology , axoplasmic transport , zebrafish , microbiology and biotechnology , motor neuron , neuroscience , anatomy , spinal cord , genetics , gene , microtubule
DYNC 1 H 1 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 DYNC 1 H 1 have been described in autosomal‐dominant C harcot– M arie– T ooth 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 DYNC 1 H 1 : c.3581 A > G (p. G ln1194 A rg) in one case and c.9142 G > A (p. G lu3048 L ys) 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 G olgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC 1 H 1 , 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.