Prevalence and spectrum of LRRC10 mutations associated with idiopathic dilated cardiomyopathy

摘要

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disease. It is the most common cause of chronic congestive heart failure and the most frequent reason for heart transplantation in young adults. There is increasing evidence demonstrating that genetic defects are involved in the pathogenesis of idiopathic DCM. Recent studies have shown that genetically defective LRRC10 predisposes animals to DCM. However, the association of LRRC10 with DCM in humans has not been reported. In the current study, the whole coding region and flanking splice junction sites of the LRRC10 gene were sequenced in 220 unrelated patients with idiopathic DCM. The available relatives of the index patients harboring identified mutations and 200 unrelated ethnically matched healthy individuals used as controls were also genotyped for LRRC10. The functional effect of the LRRC10 mutations was analyzed in silico. As a result, two novel heterozygous LRRC10 mutations, p.L41V and p.L163I, were identified in two families with DCM, respectively, with a mutational prevalence of similar to 0.91%. Genetic analyses of the pedigrees showed that in each family, the mutation co-segregated with DCM was transmitted as an autosomal dominant trait with complete penetrance. The missense mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across various species. Functional analysis in silico indicated that the LRRC10 mutations were causative. This study firstly reports the association of LRRC10 mutations with enhanced susceptibility to DCM in humans, which provides novel insight into the molecular mechanism underpinning DCM, and contributes to the development of novel prophylactic and therapeutic strategies for DCM.