Le mystère de la dystrophie myotonique de Steinert reste entier : amplification d'un CTG mais plusieurs gènes impliqués dans la pathologie ?

Abstract

Les cinq dernières années ont été marquées par la découverte d’un mécanisme moléculaire de maladies génétiques, encore inédit, celui des triplets répétés instables. Cette anomalie moléculaire qui montre une forte propension à l’expansion d’une génération à l’autre a permis d’expliquer au niveau moléculaire le phénomène d’anticipation. La dystrophie myotonique de Steinert, maladie musculaire la plus fréquente de l’adulte, appartient à cette famille, mais elle est la seule à être associée à l’expansion d’un triplet CTG, située dans la région 3’ non traduite (3’UTR) du gène DMPK sur le chromosome 19. Par-delà une corrélation entre la taille du triplet et la gravité de la maladie, on distingue de multiples formes cliniques. L’abolition de l’expression de l’allèle DMPK, porteur d’une amplification supérieure à 700 CTG, ne semble pas capable à elle seule d’expliquer l’augmentation de la gravité au-delà de ce seuil. L’expansion de la répétition CTG pourrait perturber également l’expression de gènes contigus, ou bien, la région 3’UTR acquérant de nouvelles propriétés, un gain de fonction pourrait dérégler l’expression d’autres gènes.

Myotonic dystrophy (DM) is one of a growing number of genetic disorders associated with a triplet repeat dynamic mutation discovered during the last five years. The intergenerational increase in size represents the molecular basis of the long debated phenomenon known as anticipation, an increase of the severity through consecutive generations. Myotonic dystrophy (DM) is the most frequent autosomal dominant muscular dystrophy of adults, the symptoms of which may be numerous and diverse. The mutational event causing DM is a dynamic amplification of a repeated (CTG)n DNA motif located within the 3' untranslated region (3'UTR) of the gene encoding myotonin protein kinase DMPK. Whereas the underlying mechanisms by which other expanded triplets, GAG, CCG and GAA produce the phenotype in other diseases are rather well-understood there has hardly been any progress in answering the key question: how does the DM CTG repeat in the 3'UTR exert its effect(s)? The severe and multisystemic manifestations of myotonic dystrophy may not be a simple monogenic loss- or gain-of-function effect. There remains a question mark upon whether the expanded repeat in DM influences the DMPK gene, its RNA or its protein products by interference with transcription, alternative splicing, transport or translational efficiency of mRNA or the entire cellular context in which the DMPK is expressed. However haploinsufficiency of DMPK as a unique pathogenic mechanism has been ruled out and the mouse models clearly showed that DM is not simply due to a lack or excess of the DMPK protein since these animals lack myotonia, cataracts and the congenital form. Other neighbouring genes within this gene-dense area may also be involved. An alternative hypothesis could be an alteration in the normal cellular function of the 3'UTR of the DMPK. Finally it has been put forward that the expanded DM could interact with RNA. Other animal models are therefore needed to understand the pathological consequences of this mysterious type of mutation and to reproduce the human DM phenotype for future therapy. [References: 40]