Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms

Hum Mol Genet. 2016 Jul 15;25(14):3011-3028. doi: 10.1093/hmg/ddw155. Epub 2016 Jun 23.


Atrioventricular septal defects (AVSDs) are a common severe form of congenital heart disease (CHD). In this study we identified deleterious non-synonymous mutations in two cilia genes, Dnah11 and Mks1, in independent N-ethyl-N-nitrosourea-induced mouse mutant lines with heritable recessive AVSDs by whole-exome sequencing. Cilia are required for left/right body axis determination and second heart field (SHF) Hedgehog (Hh) signaling, and we find that cilia mutations affect these requirements differentially. Dnah11avc4 did not disrupt SHF Hh signaling and caused AVSDs only concurrently with heterotaxy, a left/right axis abnormality. In contrast, Mks1avc6 disrupted SHF Hh signaling and caused AVSDs without heterotaxy. We performed unbiased whole-genome SHF transcriptional profiling and found that cilia motility genes were not expressed in the SHF whereas cilia structural and signaling genes were highly expressed. SHF cilia gene expression predicted the phenotypic concordance between AVSDs and heterotaxy in mice and humans with cilia gene mutations. A two-step model of cilia action accurately predicted the AVSD/heterotaxyu phenotypic expression pattern caused by cilia gene mutations. We speculate that cilia gene mutations contribute to both syndromic and non-syndromic AVSDs in humans and provide a model that predicts the phenotypic consequences of specific cilia gene mutations.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axonemal Dyneins / biosynthesis
  • Axonemal Dyneins / genetics*
  • Body Patterning / genetics
  • Cilia / drug effects
  • Cilia / genetics*
  • Disease Models, Animal
  • Ethylnitrosourea / toxicity
  • Exome / genetics
  • Gene Expression Regulation
  • Heart / physiopathology
  • Heart Septal Defects / genetics*
  • Heart Septal Defects / pathology
  • Hedgehog Proteins / biosynthesis
  • Hedgehog Proteins / genetics
  • Humans
  • Mice
  • Mutation
  • Proteins / genetics*
  • Signal Transduction / genetics


  • Hedgehog Proteins
  • MKS1 protein, human
  • Proteins
  • Axonemal Dyneins
  • DNAH11 protein, human
  • Ethylnitrosourea

Supplementary concepts

  • Atrioventricular Septal Defect