title: Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development.
abstract: 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.
authors.affiliation: Neuromuscular and Molecular Medicine Unit, Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorillo
authors.forename: Francesca
authors.initials: F
authors.lastname: Moro
authors.forename: Julie
authors.initials: J
authors.lastname: Yi
authors.forename: Sarah
authors.initials: S
authors.lastname: Weil
authors.forename: Giacomo
authors.initials: G
authors.lastname: Brisca
authors.forename: Guja
authors.initials: G
authors.lastname: Astrea
authors.forename: Mariasavina
authors.initials: M
authors.lastname: Severino
authors.forename: Alessandro
authors.initials: A
authors.lastname: Romano
authors.forename: Roberta
authors.initials: R
authors.lastname: Battini
authors.forename: Andrea
authors.initials: A
authors.lastname: Rossi
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Richard
authors.initials: R
authors.lastname: Vallee
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D006801:Humans; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D011487:Protein Conformation; D055815:Young Adult
chemical_list: C511240:DYNC1H1 protein, human; D056445:Cytoplasmic Dyneins
keywords: DYNC1H1; SMA-LED; abnormal cortical development; distal SMA