HAND2 loss-of-function mutation causes familial dilated cardiomyopathy.

As two members of the basic helix-loop-helix family of transcription factors, HAND1 and HAND2 are both required for the embryonic cardiogenesis and postnatal ventricular structural remodeling. Recently a HAND1 mutation has been reported to cause dilated cardiomyopathy (DCM). However, the association of a HAND2 mutation with DCM is still to be ascertained. In this research, the coding regions and splicing junction sites of the HAND2 gene were sequenced in 206 unrelated patients affected with idiopathic DCM, and a new heterozygous HAND2 mutation, NM_021973.2: c.199G > T; p.(Glu67*), was discovered in an index patient with DCM. The nonsense mutation was absent in 300 unrelated, ethnically-matched healthy persons. Genetic scan of the mutation carrier's family members revealed that the genetic mutation co-segregated with DCM, which was transmitted in an autosomal dominant fashion, with complete penetrance. Functional deciphers unveiled that the mutant HAND2 protein had no transcriptional activity. In addition, the mutation abrogated the synergistic transcriptional activation between HAND2 and GATA4 or between HAND2 and NKX2.5, two other cardiac transcription factors that have been implicated in DCM. These research findings firstly suggest HAND2 as a novel gene predisposing to DCM in humans, which adds novel insight to the molecular pathogenesis of DCM, implying potential implications in the design of personized preventive and therapeutic strategies against DCM.