Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics.
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.
Meng
Haijin
H
Department of Medicine, Cardiology Division, University of California-Los Angeles, Los Angeles, CA 90095, USA. hmeng@mednet.ucla.edu
Vera
Iset
I
Che
Nam
N
Wang
Xuping
X
Wang
Susanna S
SS
Ingram-Drake
Leslie
L
Schadt
Eric E
EE
Drake
Thomas A
TA
Lusis
Aldons J
AJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002114:Calcinosis / Q000235:genetics*; D005786:Gene Expression Regulation; D023281:Genomics; D006331:Heart Diseases / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009206:Myocardium / Q000378:metabolism*; D053495:Osteopontin / Q000096:biosynthesis; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D053495:Osteopontin; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; C504743:Abcc6 protein, mouse; C525719:Bmp2 protein, mouse