NULL MUTATION IN THE DESMIN GENE GIVES RISE TO A CARDIOMYOPATHY

A null mutation in the desmin gene has been introduced into the germ l ine of mice. Such mice develop and reproduce normally proving that des min is not needed either for the formation of the heart or the alignme nt of functioning myofibrils, However, cardiovascular lesions and a sk eletal myopathy were observed in growing and adult mice. In the presen t study we have carried out a detailed analysis of these cardiac lesio ns. Homozygous mutant mice, which were confirmed to lack expression of desmin mRNA and desmin protein in the heart, were revealed by electro n microscopy to contain degenerating cardiomyocytes as early as 5 days post-partum, At 10 days post-partum and onwards the degeneration of c ardiomyocytes gave rise to areas with an accumulation of macrophages, fibrosis and calcification preferentially in the inter-ventricular sep tum and the free wall of the right ventricle. The localization of the lesions mainly to these sites suggested that it is not the work. load and contractions per se which were the pathogenic events leading to th e cardiomyopathy. It might be that stress related to lengthening of th e myocytes occur more in the right ventricle than in the left. At the ultrastructural level changes in the intercalated discs, disruption of the sarcolemma and supercontraction of myofibrils seemed to be the ke y events leading to cardiomyocyte death. Thus, the intermediate filame nts are required to maintain the basic integrity of cardiomyocytes and especially the link between the intermediate filaments and the sarcol emma appear more important than previously realized. (C) 1997 Academic Press Limited.