STRUCTURAL AND FUNCTIONAL BASES OF LISSENCEPHALY

We propose a study of the molecular mechanisms of type I lissencephaly, a human genetic disease. Mutations occurring by pure chance in one of the two copies of the Lis1 gene in the human genome cause a condition of haploinsufficiency. This word implies a significant reduction in the amounts of gene product, whose levels are insufficient to ensure complete functionality, giving rise to the manifestation of the disease. In the case of lissencephaly, the reduction in the expression of Lis1 is due to the fact that a functional gene product can only be expressed from the non-mutated Lis1 gene. Lis1 haploinsufficiency has dire effects on neuronal developments during embryogenesis. The cerebral cortex develops late during embryogenesis using a process that entails the replication of the neuronal precursor cells and their subsequent migration through the cortex. The classical ‘folded’ appearance of the human brain originates from this process. In lissencephaly, different aspects of the development of the human cerebral cortex are impaired, resulting in an abnormal ‘unfolded’ brain (lissencaphaly literally means ‘smooth brain’) and an aberrant histology. The Lis1 gene product is a protein also named Lis1. The Lis1 protein is involved in several cellular processes that include the division of chromosomes and the migration of cells. A decrease in the levels of functional Lis1 protein is toxic for neuronal precursor cells, which fail to complete their process of division and migration required for normal brain development. Because the formation of the cerebral cortex represents the last part of embryonic development, lissencephaly is often compatible with birth, and it manifests itself with mental retardation, frequent seizures, and is often fatal during infancy.