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Genetic mouse models of nephrolithiasis

Stechman, Michael James (2010)
M.D. thesis, University of Birmingham.

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Nephrolithiasis is a common disorder of multifactorial aetiology. Although most patients have a family history, the underlying genetic causes are largely unknown. To identify novel genes for nephrolithiasis, large-scale radiological and biochemical screens of male mice derived from an N-ethyl-N-nitrosourea-mutagenesis (ENU) programme were performed. This identified models for genetic renal calcification (Rcalc1) and genetic hypercalciuria (Hcalc1). Rcalc1, an ENU-induced mutant with renal opacities on X-ray and histological renal papillary calcification, exhibited autosomal dominant transmission with reduced penetrance. Linkage analysis mapped the Rcalc1 locus to a ~1.1-Mbp region on mouse chromosome 17A3.3, a novel calcification locus containing 30 genes. Urine and plasma biochemistry did not identify a biochemical abnormality associated with Rcalc1, but cDNA microarrays identified transcriptional alterations in genes involved in apoptosis and lipid metabolism. Hcalc1, an ENU-mutant with 24-hour urinary calcium 10x normal, renal stones and diffuse renal calcification on histological analysis, was found to be due to a dominant Ser682Pro transient receptor potential subfamily V, member 5 (Trpv5) mutation. Trpv5 is involved in Vitamin D-mediated renal calcium reabsorption. In summary, this work has identified two novel ENU mouse models for autosomal dominant renal calcification which will further contribute to the study of the genetic basis of renal stones.

Type of Work:M.D. thesis.
Supervisor(s):Thakker, Rajesh
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Division of Medical Sciences
Additional Information:

The following published papers are based on this research: Stechman MJ et al. Establishing normal plasma and 24-hour urinary biochemistry ranges in C3H, BALB/c and C57BL/6J mice following acclimatization in metabolic cages. Lab Anim. 2010 Jul;44(3):218-25 PMID: 20457824 Stechman MJ, Loh NY, Thakker RV. Genetic causes of hypercalciuric nephrolithiasis. Pediatr Nephrol. 2009 Dec;24(12):2321-32. PMID: 18446382; PMCID: PMC2770137 Stechman MJ, Loh NY, Thakker RV. Genetics of hypercalciuric nephrolithiasis: renal stone disease. Ann N Y Acad Sci. 2007 Nov;1116:461-84. PMID: 17872384 4

Subjects:QH426 Genetics
RC Internal medicine
Institution:University of Birmingham
Library Catalogue:Check for printed version of this thesis
ID Code:1116
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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