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Semin Cell Dev Biol. 2018 Apr;76:33-75. doi: 10.1016/j.semcdb.2017.09.031. Epub 2017 Oct 11.

Genetics and mechanisms leading to human cortical malformations.

Author information

1
INSERM UMR-S 839, 17 Rue du Fer à Moulin, Paris 75005, France; Sorbonne Universités, Université Pierre et Marie Curie, 4 Place Jussieu, Paris 75005, France; Institut du Fer à Moulin, 17 Rue du Fer à Moulin, Paris 75005, France.
2
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; INSERM UMR 1163, Embryology and Genetics of Congenital Malformations, France.
3
INSERM UMR-S 839, 17 Rue du Fer à Moulin, Paris 75005, France; Sorbonne Universités, Université Pierre et Marie Curie, 4 Place Jussieu, Paris 75005, France; Institut du Fer à Moulin, 17 Rue du Fer à Moulin, Paris 75005, France. Electronic address: fiona.francis@inserm.fr.

Abstract

Cerebral cortical development involves a complex series of highly regulated steps to generate the laminated structure of the adult neocortex. Neuronal migration is a key part of this process. We provide here a detailed review of cortical malformations thought to be linked to abnormal neuronal migration. We have focused on providing updated views related to perturbed mechanisms based on the wealth of genetic information currently available, as well as the study of mutant genes in animal models. We discuss mainly type 1 lissencephaly, periventricular heterotopia, type II lissencephaly and polymicrogyria. We also discuss functional classifications such as the tubulinopathies, and emphasize how modern genetics is revealing genes mutated in atypical cases, as well as unexpected genes for classical cases. A role in neuronal migration is revealed for many mutant genes, although progenitor abnormalities also predominate, depending on the disorder. We finish by describing the advantages of human in vitro cell culture models, to examine human-specific cells and transcripts, and further mention non-genetic mechanisms leading to cortical malformations.

KEYWORDS:

Atypical rare mutations; Cortical malformations; Exome sequencing; Heterotopia; Human in vitro cultures; Lissencephaly; Microcephaly; Neuronal migration; Polymicrogyria; Tubulinopathies; ZIKV

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