title: Fine mapping of Dyscalc1, the major genetic determinant of dystrophic cardiac calcification in mice.
abstract: Calcification of severely dystrophic muscle is occasionally observed in targeted mouse models of muscular dystrophy and cardiomyopathy. Intracellular calcium deposition occurs in necrotic myocytes in the absence of plasma calcium and phosphate imbalances. In the heart, this recessive trait is referred to as dystrophic cardiac calcinosis (DCC). We identified previously Dyscalc1, a major genetic determinant of DCC, in a 15.2-Mbp region on proximal chromosome 7. We report now further steps toward the identification of the Dyscalc1 gene by reverse genetics. Transferring the Dyscalc1 locus from susceptible mouse strain C3H/He onto a resistant C57BL/6 strain background, we generated congenic inbred strains B6.C3-(D7Mit56-D7Mit230) and B6.C3-(D7Nds5-D7Mit230). Three days after myocardial freeze-thaw injury, both strains exhibited calcification of necrotic lesions, confirming the pathogenetic relevance of Dyscalc1. Analysis of two (129S1 x C57BL/6) x 129S1 backcrosses allowed mapping of Dyscalc1 more precisely to a region spanning 0.76 Mbp between genes Fgf21 (39.70 Mbp) and Myod1 (40.46 Mbp). This interval contains 31 known and putative genes in three large, ancestral haplotypes shared by susceptible strains C3H/He, 129S1, and DBA/2. Thus we were able to exclude previously proposed candidate genes Bax and Hrc. Instead, a potential candidate may be the gene encoding the ATP-binding cassette C6. Mutations in the orthologous human ABCC6 gene cause pseudoxanthoma elasticum, or Gronblad-Strandberg syndrome, an elastic tissue disorder with cardiovascular calcifications.
authors.affiliation: Division of Cardiology, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Korff
authors.forename: Frank
authors.initials: F
authors.lastname: Schoensiegel
authors.forename: Nora
authors.initials: N
authors.lastname: Riechert
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Boris T
authors.initials: BT
authors.lastname: Ivandic
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002114:Calcinosis / Q000235:genetics* / Q000473:pathology; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009154:Mutation; D011561:Pseudoxanthoma Elasticum / Q000235:genetics; D040641:Quantitative Trait Loci
chemical_list: D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human; C504743:Abcc6 protein, mouse