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BIOLOGICAL SCIENCES / GENETICS
Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics
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Departments of *Medicine, Cardiology Division, Pathology and Laboratory Medicine, and ||Microbiology, Immunology, Molecular Genetics, Medicine, and Human Genetics, University of California, Los Angeles, CA 90095; Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461; and ¶Rosetta Inpharmatics LLC, Merck & Co., Inc., Seattle, WA 98109
Edited by Kathryn V. Anderson, Sloan–Kettering Institute, New York, NY, and approved January 18, 2007 (received for review August 31, 2006)
The genetic factors contributing to the complex disorder of myocardial calcification are largely unknown. Using a mouse model, we fine-mapped the major locus (Dyscalc1) contributing to the dystrophic cardiac calcification (DCC) to an 840-kb interval containing 38 genes. We then identified the causal gene by using an approach integrating genetic segregation and expression array analyses to identify, on a global scale, cis-acting DNA variations that perturb gene expression. By studying two intercrosses, in which the DCC trait segregates, a single candidate gene (encoding the ATP-binding cassette transporter ABCC6) was identified. Transgenic complementation confirmed Abcc6 as the underlying causal gene for Dyscalc1. We demonstrate that in the cross, the expression of Abcc6 is highly correlated with the local mineralization regulatory system and the BMP2-Wnt signaling pathway known to be involved in the systemic regulation of calcification, suggesting potential pathways for the action of Abcc6 in DCC. Our results demonstrate the power of the integrative genomics in discovering causal genes and pathways underlying complex traits.
expression quantitative trait locus | transgenic | positional cloning | osteopontin
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0607620104/DC1.
To whom correspondence may be addressed. E-mail: hmeng{at}mednet.ucla.edu or jlusis{at}mednet.ucla.edu
© 2007 by The National Academy of Sciences of the USA
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