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J. Biol. Chem., Vol. 283, Issue 12, 7608-7615, March 21, 2008

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An Alternative Splice Variant in Abcc6, the Gene Causing Dystrophic Calcification, Leads to Protein Deficiency in C3H/He Mice^*

Zouhair Aherrahrou¹, Lars C. Doehring, Eva-Maria Ehlers, Henrike Liptau, Reinhard Depping, Patrick Linsel-Nitschke, Piotr M. Kaczmarek, Jeanette Erdmann, and Heribert Schunkert

From the Department of Medicine II and the Institute of Physiology, University of Luebeck, 23538 Luebeck, Germany

Dystrophic cardiac calcification (DCC) is an autosomal recessive trait characterized by calcium phosphate deposits in myocardial tissue. The Abcc6 gene locus was recently found to mediate DCC; however, at the molecular level the causative variants remain to be determined. Examining the sequences of Abcc6 cDNA in DCC-resistant C57BL/6 and DCC-susceptible C3H/He mice, we identified a missense mutation (Cys to Thr at codon 619, rs32756904) at the 3'-border of exon 14 that creates an additional donor splice site (GT). Accordingly, an alternative transcript variant was detected, lacking the last 5 bp of exon 14 (-AGG(C/T)GCTgtga-) in DCC-susceptible C3H/He mice that carry the Thr allele. The 5-bp deletion was found to result in premature termination at codon 684, in turn leading to protein deficiency in DCC-susceptible mouse tissue as well as in cells transfected with Abcc6 cDNA lacking the last 5 bp of exon 14. All mouse strains that were found to carry the Thr allele, including C3H/He, DBA/2J, and 129S1/SvJ, were also found to be positive for DCC. In summary, we identified a splice variant leading to a 5-bp deletion in the Abcc6 transcript that gives rise to protein deficiency both in vivo and in vitro. The fact that all mouse strains that carry the deletion also develop dystrophic calcifications further suggests that the underlying splice variant affects the biological function of MRP6 protein and is a cause of DCC in mice.

Received for publication, October 5, 2007 , and in revised form, January 11, 2008.

^* This work was supported by Forschungsfoerderung der Medizinischen Fakul taet Lübeck 2003 (J14-2003) (to Z. A.), Bundesministerium für Bildung und Forschung (National Genome Network 2 (NGFN2) (01GS0418) (to H. S. and J. E.), and the European Union-sponsored project Cardiogenics. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Medizinische Klinik II, Universitaet zu Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany. Tel.: 49-451-500-6007; Fax: 49-451-500-6437; E-mail: Zouhair.Aherrahrou{at}uk-sh.de.

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