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

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., and Lo, Cecilia W. (2015) Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature, 521 (7553). pp. 520-524.

[img] PDF (Published Version) - Published Version
Restricted to Repository staff only

View at Publisher Website:


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 inhumanfetuses(2,3). Agenetic contributionis 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 ciliatransduced 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.

Item ID: 60716
Item Type: Article (Research - C1)
ISSN: 1476-4687
Copyright Information: Copyright © 2015 Macmillan Publishers Limited
Funders: National Heart, Lung, and Blood Institute (NHLBI), National Institute of Mental Health (NIMH), National Human Genome Research Institute (NHGRI), University of Pittsburgh School of Medicine
Projects and Grants: NHLBI U01HL098180, NHLBI U01HL098188, NIMH R01MH094564, NHGRI HG000330
Date Deposited: 23 Oct 2019 12:36
FoR Codes: 06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 40%
06 BIOLOGICAL SCIENCES > 0606 Physiology > 060603 Animal Physiology Systems @ 30%
11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 30%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
Downloads: Total: 1
More Statistics

Actions (Repository Staff Only)

Item Control Page Item Control Page