HAND2 loss-of-function mutation causes familial dilated cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Developmental Biology

Background:

• Basic helix-loop-helix transcription factors HAND1 and HAND2 are crucial for heart development and maintenance.
• While HAND1 mutations are linked to dilated cardiomyopathy (DCM), the role of HAND2 mutations in DCM remains unclear.

Purpose of the Study:

• To investigate the association between HAND2 gene mutations and idiopathic DCM.
• To identify novel genetic factors contributing to the molecular pathogenesis of DCM.

Main Methods:

• Sequencing of HAND2 gene coding regions and splicing junctions in 206 DCM patients.
• Genotyping of mutation carriers' families and a control cohort (300 healthy individuals).
• Functional assays to assess the impact of the identified HAND2 mutation on transcriptional activity.

Main Results:

• A new heterozygous nonsense mutation (c.199G>T; p.(Glu67*)) in HAND2 was identified in an index DCM patient.
• This mutation was absent in healthy controls and co-segregated with DCM in the family, exhibiting autosomal dominant inheritance with complete penetrance.
• The mutant HAND2 protein demonstrated loss of transcriptional activity and impaired synergistic activation with GATA4 and NKX2.5.

Conclusions:

• This study identifies HAND2 as a novel gene predisposing to human DCM.
• The findings provide new insights into the molecular mechanisms underlying DCM.
• This research may inform personalized preventive and therapeutic strategies for DCM.