Neuropathological Hallmarks of Brain Malformations in Extreme Phenotypes Related to DYNC1H1 Mutations.
Fiche publication
Date publication
mars 2017
Journal
Journal of neuropathology and experimental neurology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHELLY Jamel
Tous les auteurs :
Laquerriere A, Maillard C, Cavallin M, Chapon F, Marguet F, Molin A, Sigaudy S, Blouet M, Benoist G, Fernandez C, Poirier K, Chelly J, Thomas S, Bahi-Buisson N
Lien Pubmed
Résumé
Dyneins play a critical role in a wide variety of cellular functions such as the movement of organelles and numerous aspects of mitosis, making it central player in neocortical neurogenesis and migration. Recently, cytoplasmic dynein-1, heavy chain-1 (DYNC1H1) mutations have been found to cause a wide spectrum of brain cortical malformations. We report on the detailed neuropathological features of brain lesions from 2 fetuses aged 36 and 22 weeks of gestation (WG), respectively, carrying de novo DYNC1H1 mutations, p.Arg2720Lys and p.Val3951Ala and presenting the most severe phenotype reported to date. Analysis using the Dictyostelium discoideum dynein motor crystal structure showed that the mutations are both predicted to have deleterious consequences on the function of the motor domain. Both fetuses showed a similar macroscopic and histological brain malformative complex associating bilateral fronto-parietal polymicrogyria (PMG), dysgenesis of the corpus callosum and of the cortico-spinal tracts, along with brainstem and cerebellar abnormalities. Both exhibited extremely severe disrupted cortical lamination. Immunohistochemical studies provided the evidence for defects in cell proliferation and postmitotic neuroblast ability to exit from the subventricular zone resulting in a failure of radial migration toward the cortical plate, thus providing new insights for the understanding of the pathophysiology in these cortical malformations.
Mots clés
Adult, Brain, abnormalities, Cell Culture Techniques, Cytoplasmic Dyneins, genetics, Female, Fetus, Humans, Mutation, genetics, Neuropathology, Phenotype, Pregnancy, Protein Structure, Secondary
Référence
J. Neuropathol. Exp. Neurol.. 2017 03 1;76(3):195-205