SFEBES2009 Poster Presentations Diabetes and metabolism (59 abstracts)
Mice harbouring the familial juvenile hyperuricaemic nephropathy disease-causing uromodulin (Tamm--Horsfall glycoprotein) mutation Cys125Arg, have a urine concentrating defect, progressive renal failure, and altered uric acid handling
Sian Piret 1 , Anita Reed 1 , M Andrew Nesbit 1 , Tertius Hough 2 , Liz Bentley 2 , Roger Cox 2 & Rajesh Thakker 1
1University of Oxford, OCDEM, Oxford, UK; 2MRC Mammalian Genetics Unit and Mary Lyon Centre, Harwell, UK.
Familial juvenile hyperuricaemic nephropathy (FJHN), an autosomal dominant disorder characterised by raised serum urate, reduced fractional excretion of uric acid (FEUA), a urine concentrating defect, and progressive renal failure, is caused by mutations in the UMOD gene, encoding uromodulin (Tamm–Horsfall glycoprotein). The FJHN-causing UMOD mutations are missense mutations (>90%) or inframe deletions (<10%), and none result in prematurely truncated proteins, indicating the disorder is unlikely to be due to a loss of function. We therefore engineered a knock-in mouse harbouring the FJHN-causing Cys125Arg mutation. Mice were maintained in accordance with UK license restrictions. Wild type, heterozygous (Umod+/125R) and homozygous (Umod125R/125R) mutant mice, aged 8 weeks or 6 months, were investigated in metabolic cages. Umod+/125R and Umod125R/125R mice had a low urine osmolality (P<0.02) with a normal or high plasma osmolality, and were polyuric (P<0.02), and polydipsic (P<0.001). Eight week old Umod125R/125R mice had significantly raised plasma urea (P<0.02), whilst by 6 months of age, Umod+/125R and Umod125R/125R mice had developed significantly raised plasma urea (P<0.0001), and Umod125R/125R mice had elevated plasma creatinine (P<0.005), consistent with progressive renal failure. Six month old Umod125R/125R mice also had significantly raised plasma alkaline phosphatase (P<0.01), and a significantly reduced FEUA (P<0.001), which was not associated with a raised plasma uric acid, due to the presence of the enzyme uricase in mice. Thus, these uromodulin knock-in mice have phenotypic similarities to FJHN patients, in having a urinary concentrating defect, progressive renal failure, and reduced FEUA. Our study opens the way for further in vivo investigations to elucidate the pathophysiological basis of FJHN and its associated renal failure.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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