Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is the most prevalent cause of non-ischemic cardiac failure and the commonest indication for cardiac transplantation. Compelling evidence highlights the pivotal roles of genetic defects in the occurrence of DCM. Nevertheless, the genetic determinants underpinning DCM remain largely obscure. In this study, the coding regions of ISL1, which encodes a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling, were sequenced in 216 unrelated patients with DCM, and a novel heterozygous ISL1 mutation, NM_002202.2: c.631A>T; p.(Lys211*), was identified in a proband. The mutation, which co-segregated with DCM in the family, was absent in 238 unrelated controls, as well as in the Genome Aggregation and the Exome Aggregation Consortium population databases. Functional analyses unveiled that the mutant ISL1 protein lost transcriptional activity alone or in synergy with TBX20 or GATA4, two other transcription factors associated with DCM. These findings indicate ISL1 as a new gene of DCM.