SFEBES2007 Poster Presentations Bone (16 abstracts)
Mapping of a renal calcification locus to a 5-megabase region on mouse chromosome 17B1/B2
Michael Stechman 1 , Nellie Loh 1 , Anita Reed 1 , Bushra Ahmad 1 , Michelle Stewart 2 , Terry Hacker 3 , Sara Wells 2 , Tertius Hough 2 , Liz Bentley 3 , Brian Harding 1 , Paul Christie 1 , Roger Cox 3 , Neil Dear 2 , Steve Brown 3 & Rajesh Thakker 1
1Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; 2Mary Lyon Centre, Medical Research Council, Harwell, Oxfordshire, United Kingdom; 3MRC Mammalian Genetics Centre, Medical Research Council, Harwell, Oxfordshire, United Kingdom.
Calcium-containing renal stones, which affect 7% of adults, may be associated with endocrine and metabolic disorders that include primary hyperparathyroidism, renal tubular acidosis, hypercalciuria and hyperoxaluria. In addition, ∼40% of patients with stones have a familial history, although the genetic defects remain to be elucidated. To facilitate this, we have established a mouse model for renal calcification, designated Rcalc1, and determined its chromosomal localisation. Mice were kept in accordance with UK Home Office welfare guidelines and project license restrictions. The founder of Rcalc1 was identified by radiological investigations for renal opacities of 1745 twelve-month old progeny of N-ethyl-N-nitrosourea mutagenised male BALB/c mice. Founder sperm was used to artificially inseminate C3H oocytes and 158-second generation (G2) progeny derived. Histological examination using haematoxylin-eosin, and von Kossa stained renal sections from 18–34 week-old G2 mice revealed collecting duct calcification in 52 mice, yielding an affected: unaffected ratio of 0.5:1 which is consistent with an autosomal dominant inheritance with reduced penetrance. A genome-wide search using chromosome-specific sets of 60 single nucleotide polymorphisms at 20–30 cM intervals in 13 affected mice mapped Rcalc1 to chromosome 17 with a peak LOD score of 3.91 at 0% recombination. An extended analysis using ten chromosome 17 microsatellite markers in all the affected and unaffected mice yielded a peak LOD score of 9.44, at 24% recombination, with the loci D17Mit101 and D17Mit175. An examination of recombinants defined the locus order as: 17cen-D17Mit80-(D17mit101, Rcalc1, D17Mit81)-D17Mit175-17ter. This narrows the search for Rcalc1 to a 5 Mb region that contains about 100 genes including those for Trefoil factor 1, a calcium stone inhibitor, and Retinoid receptor X beta, which is involved in Vitamin D metabolism. Thus, our studies have established a mouse model for renal calcification and identified a locus on chromosome 17B1/B2, which likely has an important role in renal calcium homeostasis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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