A functional genetic study identifies HAND1 mutations in septation defects of the human heart

Area of Science:

• Developmental Biology
• Genetics
• Cardiology

Background:

• Heart and neural crest derivatives expressed 1 (HAND1) is a vital transcription factor for mammalian heart development.
• Absence of Hand1 leads to embryonic lethality and severe cardiac abnormalities in mice, implicating it in human congenital heart disease (CHD).
• Previous studies identified a frequent loss-of-function mutation (p.A126fs) in HAND1 within hypoplastic hearts.

Purpose of the Study:

• To investigate the role of HAND1 mutations in a cohort of human hearts with septal defects.
• To correlate identified HAND1 sequence alterations with transcriptional activity and cardiac malformations.

Main Methods:

• Screening of HAND1 gene in tissue samples from human septal defects.
• Identification and characterization of sequence alterations within the HAND1 gene, particularly in the bHLH domain.
• Functional studies in yeast and mammalian cells to assess the impact of mutations on HAND1 transcriptional activity.

Main Results:

• Thirty-two sequence alterations in HAND1 were detected in septal defect samples, with 12 located in the bHLH domain.
• Several previously identified mutations (e.g., p.L28H, p.L138P) were found, alongside the absence of the frequent p.A126fs mutation in most cases.
• Functional assays demonstrated that specific HAND1 mutations, such as p.L138P, significantly reduce or abolish transcriptional activity.

Conclusions:

• HAND1 gene mutations are implicated in human heart septation defects, expanding its known role in CHD.
• The functional impact of HAND1 mutations on transcriptional activity provides a mechanistic link to cardiac malformations.
• These findings highlight HAND1 as a significant factor in human heart development and the etiology of congenital heart disease.