Novel DyneinDYNC1H1Neck 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.

Novel mutations expand the clinical spectrum of DYNC1H1 -associated spinal muscular atrophy

“…14 Two additional unrelated cases with novel DYNC1H1 mutations, located in the neck and motor domains, respectively, have been described in association with an SMA-LED phenotype and brain cortical malformation. 15 In this study, we report a large cohort of children and adults affected by SMA-LED due to DYNC1H1 mutations, expanding the clinical spectrum to include severe cases with generalized arthrogryposis and milder cases with onset in adulthood. The detection of cognitive/behavioral impairment and cortical malformations in a proportion of affected individuals demonstrates the frequent co-occurrence of central and peripheral pathology.…”

“…12,13 Malformations of cortical development (MCDs) were found in 10 individuals from 2 separate studies. 14,15 Three tail domain mutations in the mouse homolog of DYNC1H1 have been described: "legs at odd angles" (Loa), "crawling" (Cra1), and "sprawling" (Swl), 16,17 all sharing motor and sensory deficits and the Loa mice demonstrating cortical migration defects. 18 Phenotypic differences among these models and the emerging diversity of reported patients, suggests that the human DYNC1H1 clinical spectrum extends beyond SMA-LED.…”

“…DYNC1H1 sequencing. Most subjects underwent Sanger sequencing of the tail domain of DYNC1H1 (exons [5][6][7][8][9][10][11][12][13][14][15] at either the Institute of Neurology, UCL, or at Washington University in St. Louis. Twelve primer pairs were used to amplify exons and flanking intronic sequences and were sequenced bidirectionally (primer details available on request).…”

FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development

“…Remarkably, several of these additional identified genes are known to be involved in the process of neuronal migration, including Dync1h1, a dynein motor protein, and Nrcam, a neuronal cell-adhesion protein associated with psychiatric disorders such as autism (27)(28)(29). The expression of Nfia, a family member of Nfix, which has been shown to be involved in regulating the rostral migratory stream of SVZ-derived neuroblasts (30), was, like Plxna4, significantly decreased upon siRNA-mediated knockdown of FoxO6.…”

Quand le NGS aide à résoudre une énigme diagnostique

“…Un an plus tard, Harms et al [10] élargit le phénotype aux SMA-LED à transmission dominante, avec comme éléments phénotypiques un début dans l'enfance, voire congénital, une atteinte à prédominance proximale, peu évolutive dans le temps, et associée dans 30 % des cas à une défi-cience intellectuelle sans malformation corticale. L'association à de possibles malformations corticales (le plus souvent de type polymicrogyrique) sera ensuite validée dans d'autres observations [11,12], tout comme l'implication du premier motoneurone avec présence d'une paraparésie spastique, comme observé chez notre patient [13]. Enfin, on notera la coexistence possible à une cataracte plus récem-ment décrite, qu'elle soit congénitale [14] ou acquise [15].…”