Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms

Ozanna Burnicka-Turek, Jeffrey D. Steimle, Wenhui Huang, Lindsay Felker, Anna Kamp, Junghun Kweon, Michael Peterson, Roger H. Reeves, Cheryl L. Maslen, Peter J. Gruber, Xinan H. Yang, Jay Shendure, Ivan P. Moskowitz

    Research output: Contribution to journalArticlepeer-review

    42 Scopus citations


    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.

    Original languageEnglish (US)
    Pages (from-to)3011-3028
    Number of pages18
    JournalHuman molecular genetics
    Issue number14
    StatePublished - 2016

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Genetics(clinical)


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