SFEBES2007 Poster Presentations Diabetes, metabolism and cardiovascular (63 abstracts)
cDNA expression profiling studies reveal 7 differentially expressed genes on mouse chromosome 7 that may influence renal calcification in C3H/HeH inbred mice
Nellie Loh 1 , Michael Stechman 1 , Anita Reed 1 , Bushra Ahmad 1 , Michelle Stewart 2 , Terry Hacker 2 , Herbert Schulz 3 , Gabi Born 3 , Neil Dear 2 , Steve Brown 2 , Norbert Hubner 3 & Rajesh Thakker 1
1University of Oxford, Oxford, United Kingdom; 2Medical Research Council, Harwell, Oxfordshire, United Kingdom; 3Max-Delbrück-Centre for Molecular Medicine, Berlin, Germany.
Vascular calcification, occurring in organs such as heart and kidneys, is associated with increased risk of cardiovascular mortality. The underlying molecular mechanisms remain unknown. To elucidate these, we investigated C3H mice, an inbred strain susceptible to vascular, myocardial and renal calcification. Myocardial calcification in C3H mice involves 4 genetic loci, Dyscalc1-4, that map to chromosomes 7, 4, 12 and 14, respectively. Dyscalc1 contributes to myocardial and vascular calcification, but its role in renal calcification is unknown. To investigate this, we undertook 3 approaches: 1) a histological assessment for the presence of renal calcification using von Kossa staining in kidneys from 30–33 week-old C3H/HeH (n=20), BALB/c (renal calcification resistant) (n=20), G1(BALB/c × C3H/HeH) (n=6), and G2(C3H/BALB/c × C3H/HeH) (n=31) mice; 2) determination of the haplotypes using markers flanking Dyscalc1 in these mice; and 3) identification of differentially expressed genes by microarray studies using total RNA from BALB/c and C3H/HeH kidneys. Mice were kept in accordance with UK Home Office welfare guidelines and project licence restrictions. Renal calcification was detected in 100% of C3H/HeH mice, 25/31 (80.6%) of G2 mice and none of BALB/c or G1 mice, consistent with an autosomal recessive inheritance involving 2 loci (χ2 P-value=0.47). Haplotype analysis with markers flanking Dyscalc1 revealed that 14/31 (45.2%) individuals, all of whom had renal calcification, were homozygous for the C3H/HeH haplotype, and hence consistent with co-segregation of the C3H/HeH allele with the phenotype (χ2 P-value=0.0001). Microarray studies identified 7 differentially expressed genes between BALB/c and C3H/HeH mice (t-test, P-value<0.05) that map within the ∼1 Mb critical region on chromosome 7. Microarray and haplotype analyses excluded EMP-3, a proposed candidate gene for Dyscalc1, as a cause for renal calcification. Thus, our studies show that renal calcification in C3H/HeH mice is an autosomal recessive trait influenced by Dyscalc1 and at least one other locus.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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