Triplets répétés, maladies neurodégénératives et psychiatriques : mécanismes et gènes candidats.

Abstract

Initialement détectées dans le syndrome de l'X fragile, les mutations dynamiques avec expansions variables de triplets répétés polymorphes (CGG, CAG, CTG ou GAA) constituent une nouvelle classe de mutations responsables de plusieurs maladies neurodégénératives héréditaires ; elles pourraient aussi être impliquées dans les formes familiales de maladies psychiatriques multifactorielles telles que la psychose maniaco-dépressive et la schizophrénie. De nouvelles méthodes de caractérisation de ces mutations et de clonage des gènes impliqués ont été développées. L'étude détaillée des effets intracellulaires des expansions déjà identifiées permettent déjà une meilleure compréhension des mécanismes biologiques et biochimiques en jeu. Le recensement exhaustif de nouveaux triplets répétés au niveau de l'ADN génomique et des ADNe, de répétitions de glutamine au niveau des protéines, permet d'identifier des candidats à l'expansion qui pourraient être en cause dans des affections aux mécanismes génétiques encore inconnus.

Initially found to be the causative mutation for the fragile X syndrome, the expansion of polymorphic triplet repeats (CGG, GAG, CTG or GAA) in human transcripts or introns (dynamic mutations) is a new class of mutations for genetic diseases. CAG expansion in coding sequences is a generalized model for the molecular pathogenesis of several inherited neurodegenerative diseases. Dynamic mutations could also be involved in neuropsychiatric diseases such as bipolar affective disorder and schizophrenia. Over the past three years, new methodologies have been developed in order to characterize dynamic mutations in patients, as well as to rapidly clone the disease penes. The detailed analysis of known dynamic mutations and their consequences at the cellular level leads to a better understanding of the biological and biochemical mechanisms underlying these diseases. Specifically several proteins interacting with polyglutamine stretches in proteins encoded by CAG repeats in the genes of spinocerebellar ataxia 1, Huntington's disease, and dendatorubral-pallidoluysian atrophy have been identified. Protein-protein interactions may account for the selective neurodegeneration observed in each disease. The survey of potentially expanded triplet repeats in genomic DNA, cDNAs, and proteins is providing the scientific community with an increasing number of candidate genes. These approaches should also permit the putative role of dynamic mutations in neuropsychiatric diseases to be further documented. These multifactorial diseases indeed show complex clinical and genetic traits, and are probably polygenic. Large-scale testing of patients and their families is the only way to detect all mutations involved. As for therapeutic approaches, the search for lead compounds with ability to block the gains of function subsequent to glutamine expansion in neurodegenerative disease proteins may be promising. [References: 50]