An Alternative Splice Variant in Abcc6, the Gene Causing Dystrophic Calcification, Leads to Protein Deficiency in C3H/He Mice
| Autor: | Jeanette Erdmann, Patrick Linsel-Nitschke, Henrike Liptau, Reinhard Depping, Piotr M. Kaczmarek, Eva-Maria Ehlers, Heribert Schunkert, Zouhair Aherrahrou, Lars C. Doehring |
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| Rok vydání: | 2008 |
| Předmět: |
DNA
Complementary Mutation Missense Biology Biochemistry Mice Autosomal recessive trait Exon Dystrophic calcification Complementary DNA medicine Animals Missense mutation Allele Molecular Biology Gene Alleles Sequence Deletion Genetics Base Sequence Myocardium fungi Alternative splicing Calcinosis Cell Biology medicine.disease Molecular biology Alternative Splicing Amino Acid Substitution Codon Terminator ATP-Binding Cassette Transporters Multidrug Resistance-Associated Proteins Cardiomyopathies |
| Zdroj: | Journal of Biological Chemistry. 283:7608-7615 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m708290200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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