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

• Published in: Nature (London) Vol. 521; no. 7553; pp. 520 - 524
• Main Authors: Li, You, Klena, Nikolai T., Gabriel, George C., Liu, Xiaoqin, Kim, Andrew J., Lemke, Kristi, Chen, Yu, Chatterjee, Bishwanath, Devine, William, Damerla, Rama Rao, Chang, Chienfu, Yagi, Hisato, San Agustin, Jovenal T., Thahir, Mohamed, Anderton, Shane, Lawhead, Caroline, Vescovi, Anita, Pratt, Herbert, Morgan, Judy, Haynes, Leslie, Smith, Cynthia L., Eppig, Janan T., Reinholdt, Laura, Francis, Richard, Leatherbury, Linda, Ganapathiraju, Madhavi K., Tobita, Kimimasa, Pazour, Gregory J., Lo, Cecilia W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.05.2015; Nature Publishing Group
• Subjects: 14/19; 14/63; 45; 45/23; 45/70; 631/208; 64/60; Animals; Birth defects; Cardiovascular disease; Cardiovascular diseases; Cilia - diagnostic imaging; Cilia - genetics; Cilia - pathology; Cilia - physiology; Cilia and ciliary motion; Congenital diseases; Congenital heart disease; Defects; DNA Mutational Analysis; Electrocardiography; Embryos; Exome - genetics; Fetuses; Genes, Recessive; Genetic aspects; Genetic Testing; Genetics; Genotype & phenotype; Heart Defects, Congenital - diagnostic imaging; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Human populations; Humanities and Social Sciences; Humans; letter; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Mutation; Mutation - genetics; Pathogenesis; Proteins; Rodents; Science; Signal Transduction; Ultrasonography; Pennsylvania
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14269

A forward genetic screen in fetal mice to identify genes involved in congenital heart disease (CHD) reveals that a large proportion of genes associated with CHD are related to cilia and cilia-transduced cell signalling, with potential implications for the human disease. Cilia defects in congenital heart disease The identification of genes causing congenital heart disease (CHD) has been challenging, in part because of the difficulty of distinguishing pathogenic mutations from random sequence genetic variability. Cecilia Lo and colleagues have therefore used a large-scale mouse forward genetic screen with chemical mutagenesis to recover mutations causing congenital heart disease. They identify 218 mouse models of the condition and, using whole-exome sequencing, 91 recessive mutations in 61 genes. A larger than expected proportion of these genes was found to be related to cilia and cilia-transduced cell signalling. Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births 1 ; the incidence of CHD is up to tenfold higher in human fetuses 2 , 3 . A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk 4 . 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 5 , 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.