[Molecular genetics of lissencephaly and microcephaly].

Genetic malformations of the cerebral cortex are an important cause of neurological disability in children. The genes implicated in these disorders are essential for normal cerebral cortical development. Therefore, identifying these genes and studying their functions will help us further the understanding of the normal biological mechanisms of brain development. Lissencephaly and microcephaly are two groups of disorders that have been intensely studied and several causative genes within each group have been identified. Type I (classical) lissencephaly is characterized by a smooth-appearing brain with a lack or severe reduction of normal gyri. Three of its identified causative genes (LIS1, DCX and TUBA1A) are related to microtubules, which are essential for neuronal migration in the developing cerebral cortex. Microcephaly vera is a form of microcephaly with four responsible genes reported to date. Three of them (ASPM, CENPJ and CDK5RAP2) localize to the mitotic centrosome, and one (MCPH1) is implicated in cell cycle checkpoint regulation and DNA damage response. This suggests that abnormalities of neural progenitor cell division are fundamental to the pathogenesis of microcephaly vera. These genes for microcephaly vera are also suggested to have played a role in evolutionary volume expansion of the human cerebral cortex. These examples show that genetic studies of lissencephaly and microcephaly have been very fruitful in providing novel insights into various aspects of human cerebral cortical development.