Genetic mouse models of nephrolithiasis

Stechman, Michael James (2010). Genetic mouse models of nephrolithiasis. University of Birmingham. M.D.

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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: Thesis (Higher Doctorates > M.D.)
Award Type: Higher Doctorates > M.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism
Funders: Other
Other Funders: Kidney Research UK
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine


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