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HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy
Insights
A novel HAND1 gene mutation increases susceptibility to dilated cardiomyopathy (DCM) in humans. This loss-of-function mutation impairs cardiac development and function, offering new insights into DCM's molecular basis.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- The transcription factor HAND1 is vital for heart development and structural remodeling.
- HAND1 mutations are linked to congenital heart diseases, but their role in dilated cardiomyopathy (DCM) is unclear.
Purpose of the Study:
- To investigate if HAND1 gene mutations predispose individuals to idiopathic DCM.
- To characterize the functional impact of identified HAND1 mutations.
Main Methods:
- Sequencing of the HAND1 gene in 140 idiopathic DCM patients.
- Genotyping of family members and 260 healthy controls.
- Dual-luciferase reporter assay to assess HAND1 mutant function.
Main Results:
- A novel heterozygous HAND1 mutation (p.R105X) was found in a DCM family, co-segregating with the disease.
- This nonsense mutation, absent in controls, resulted in a loss-of-function HAND1 protein.
- The mutation abolished HAND1's transcriptional activity and its synergy with GATA4.
Conclusions:
- This study demonstrates the first association between HAND1 loss-of-function mutations and increased DCM susceptibility in humans.
- These findings provide new molecular insights into the pathogenesis of DCM.
Background:
The basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown.
Methods:
The whole coding region and splicing junctions of the HAND1 gene were sequenced in 140 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 260 unrelated ethnically matched healthy individuals used as controls were genotyped for HAND1. The functional effect of the mutant HAND1 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.
Results:
A novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM.
Conclusions:
This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM.
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01:39Mutations