Abstract 401: A Mutation in M2MR Gene as a Cause of Familial Dilated Cardiomyopathy

Autoantibodies against β 1 -adrenoceptor (β 1 AR) and M 2 -muscarinic receptor (M2MR) have been detected in patients with dilated cardiomyopathy (DCM). It has been reported that autoanti-bodies against the β 1 AR play an important role in the pathogenesis of familial DCM and that the expression of these autoantibodies is linked to mutation of the correlative gene. This study tested a hypothesis that expression of autoantibodies against the M2MR (anti-M2MR) contributes to the onset of DCM in Chinese families and is related to a mutation of the M2MR gene. The coding regions of the M2MR gene were screened in three unrelated families all having a history of DCM, 137 patients with sporadic DCM and 327 normal individuals by direct DNA sequencing. A disruptive single-site mutation (C722G) encoding for a cysteine to tryptophane conversion was detected in the M2MR gene of 12 subjects from 3 unrelated families with DCM. Four of these patients (36.4%) carrying the C722G mutation experienced sudden death, seven suffered from heart failure and one unaffected member demonstrateed a slight AV-block in the second family DCM (See table). The C722G mutation was not detected in other unaffected members of the three family groups, 137 patients with sporadic DCM and 327 unrelated normal individuals. Survival analysis showed that patients with the Cys176Trp mutation have a significantly poorer prognosis than non-carriers ( P 0.01). A mutation of M2MR gene was detected in all DCM-positive individuals of the family groups. The putative M2MR gene mutant appears to be inherited as an autosomal dominant trait with a phenotype characterized by sudden death, severe heart failure and AV conduction block. As the consequences of DCM are so severe, screening for the M2MR gene mutation may be warranted for individuals with a family history of this disease. To our knowledge, this is the first report linking a mutation of M2MR gene to familial DCM.