Génétique des cardiomyopathies hypertrophiques.

Abstract

La cardiomyopathie hypertrophique est une maladie cardiaque de révélation tardive, caractérisée par une hypertrophie de la paroi ventriculaire. Sa gravité est liée au risque de mort subite et à l’accroissement de la rigidité ventriculaire pouvant entraîner une insuffisance cardiaque par altération de la fonction diastolique du coeur. Des mutations dans les gènes codant pour des protéines sarcomériques en sont la cause principale, mais les mécanismes moléculaires conduisant aux cardiomyopathies hypertrophiques ne sont pas encore complètement élucidés. La très grande hétérogénéité génétique de la maladie nécessite de développer de nouvelles stratégies diagnostiques et de poursuivre la caractérisation des mutations et des phénotypes associés.

Familial hypertrophic cardiomyopathy (FHC) is characterized by left and/or right ventricular hypertrophy, preferentially affecting the interventricular septum, in the absence of other known causes that induce hypertrophy. Typical morphological changes include myocyte hypertrophy and disarray surrounding areas of loose connective tissue. Arrhythmias and premature sudden deaths are common. The clinical manifestations of FHC are numerous, ranging from benign asymptomatic course to severe heart failure and sudden death. FHC is inherited in an autosomal dominant patter. The results of molecular genetic studies have shown that all mutations found so far concern genes that encode sarcomeric proteins: three contractile proteins, the beta-myosin heavy chain, the ventricular myosin essential light chain 1 and the ventricular myosin regulatory light chain 2; three associated proteins, cardiac troponin T, cardiac troponin I, and alpha-tropomyosin; and finally one myosin-binding protein, the cardiac myosin binding protein C. These genes certainly do not represent the whole spectrum of FHC disease genes since an additional locus was reported and one might reasonably hypothesize that disease genes yet to be identified include additional components of the sarcomere. One of the next challenges is to decipher the mechanisms through which the disease results from sarcomeric gene defects. The focus of the present article is to review the current state of knowledge on (1) the organization and mutations of FHC disease genes and proteins and (2) the in vitro and in vivo functional consequences of these mutations. [References: 67]