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J Neuropathol Exp Neurol. 2017 Mar 1;76(3):195-205. doi: 10.1093/jnen/nlw124.

Neuropathological Hallmarks of Brain Malformations in Extreme Phenotypes Related to DYNC1H1 Mutations.

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Department of Pathology, Normandy Centre for Genomic and Personalized Medicine, Normandie University, Rouen University Hospital, NeoVasc Team, UNIROUEN, Inserm U1245, Rouen, France.
Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris and INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Paris France.
Pediatric Neurology, Necker Enfants Malades University Paris Hospital, APHP, Paris, France.
Pathology Laboratory, Caen University Hospital, Caen France.
Service de Génétique Pôle Biologie et Pharmacie Rouen University Hôpital, France.
Clinical Genetics, Hôpital de La Timone, APHM, Marseille University Hospital, Marseille France.
Department of Radiology, Caen University Hospital, Caen France.
Department of Obstetrics and Gynaecology, Caen University Hospital, Caen France.
Department of Pathology and Neuropathology, La Timone University Hospital, Marseille, France.
Inserm, U1016, Institut Cochin, Paris, France.
CNRS, UMR8104, Paris, France.
Denis Diderot School of Medicine, Sorbonne-Paris Cité University, Paris, France.
IGBMC, INSERM U964, CNRS UMR 7104, Université de Strasbourg, Illkirch, France.
Pôle de Biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.


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.


Brain pathology; DYNC1H1 gene mutations; Microcephaly; Neuritic outgrowth; Path finding; Polymicrogyria

[Indexed for MEDLINE]

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