Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms

Area of Science:

• Developmental Biology
• Genetics
• Cardiology

Background:

• Atrioventricular septal defects (AVSDs) represent a severe and common form of congenital heart disease (CHD).
• Cilia play critical roles in embryonic development, including left/right body axis determination and signaling pathways essential for heart formation.

Purpose of the Study:

• To identify genetic mutations causing AVSDs.
• To investigate the role of cilia genes in heart development and left/right axis formation.
• To elucidate the differential impact of cilia gene mutations on AVSDs and heterotaxy.

Main Methods:

• Whole-exome sequencing to identify mutations in mouse models.
• Generation of N-ethyl-N-nitrosourea-induced mouse mutant lines with heritable recessive AVSDs.
• Whole-genome transcriptional profiling of the second heart field (SHF).

Main Results:

• Deleterious mutations in cilia genes Dnah11 and Mks1 were identified in mouse lines with AVSDs.
• Dnah11 mutations caused AVSDs with heterotaxy but did not affect SHF Hedgehog (Hh) signaling.
• Mks1 mutations disrupted SHF Hh signaling and caused AVSDs without heterotaxy.
• SHF expression of cilia structural and signaling genes, but not motility genes, correlated with phenotypic outcomes.

Conclusions:

• Cilia gene mutations differentially affect left/right axis determination and SHF Hh signaling, leading to distinct AVSD phenotypes.
• A two-step model of cilia function accurately predicts the observed AVSD and heterotaxy patterns.
• Cilia gene mutations are implicated in both syndromic and non-syndromic AVSDs in humans, providing a predictive model for phenotypic consequences.