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Nature. 2015 May 28;521(7553):520-4. doi: 10.1038/nature14269. Epub 2015 Mar 25.

Global genetic analysis in mice unveils central role for cilia in congenital heart disease.

Author information

1
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
2
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
3
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
4
1] Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15206, USA [2] Intelligent Systems Program, School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 16260, USA.
5
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
6
The Heart Center, Children's National Medical Center, Washington DC 20010, USA.

Abstract

Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.

PMID:
25807483
PMCID:
PMC4617540
DOI:
10.1038/nature14269
[Indexed for MEDLINE]
Free PMC Article
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