Journal article
Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice
WS Stevenson, CD Hyland, JG Zhang, PO Morgan, TA Willson, A Gill, AA Hilton, EM Viney, M Bahlo, SL Masters, S Hennebry, SJ Richardson, NA Nicola, D Metcalf, DJ Hilton, AW Roberts, WS Alexander
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2010
Abstract
With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5-hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5- ureidoimidazoline decarboxylase inmost vertebrate species. A point mutation in the gene encoding mouse HIU hydrolase, Urah, that perturbed uric acid metabolism within the liver was discovered during a mutagenesis screen in mice. The predicted substitution of cysteine for tyrosine in a conserved helical region of the mutantencoded HIU hydrolase resulted in undetectable protein expression. Mice homozygous for this mutation developed elevated platelet counts secondary to excess thrombopoietin product..
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Awarded by Australian National Health and Medical Research Council of Australia
Funding Acknowledgements
We thank Jason Corbin and Janelle Lochland for technical assistance and David De Sousa and Malcolm McConville for helpful discussions and input. This work was supported by Program Grant 461219, fellowships (to D.J.H.,W.S.A., N.A.N., A.W.R., and M.B.), a scholarship (to W.S.S.), and Independent Research Institutes Support Scheme Grant 361646 from the Australian National Health and Medical Research Council of Australia; a Fellowship from the Cancer Council, Victoria (to D.M.); the Australian Cancer Research Fund; a Victorian State Government Operational Infrastructure Support grant; and MuriGen Pty. Ltd.