[Multifactorial disorder: molecular and evolutionary insights of uric acid nephrolithiasis].
Nephrolithiasis is a common multifactorial disorder affecting about 10% of the Western populations and it is characterized by the presence of small crystals and stones in the urinary tract. Uric acid nephrolithiasis (UAN) accounts for 20% of all stones but its prevalence varies between countries. Nephrolithiasis is likely caused by several factors but a genetic component has clearly been demonstrated. While studying an ancient founder population in Sardinia, we recently identified a susceptibility locus for UAN on chromosome 10. In this region we identified a missense mutation in a specific isoform of a novel gene is strongly associated with UAN. Through a comparative genomic approach, we did not found a mouse homolog even if we were able to identify the corresponding genomic region, while in Old World monkey we found a canonical gene structure with several stop codons preventing protein production. We detected expression in New World monkeys while in humans we observe a functional protein. It seems, therefore, that, to avoid human disease, a fierce selection worked to develop a renal-haematic urate homeostasis system against excessive hyperuricaemia. ZNF365 emerged during primate evolution and assumed its role in parallel with the disappearance of uricase, probably against a disadvantageous excessive hyperuricaemia.
Gianfrancesco
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Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche, Avellino, Italy. fgianfrancesco@isa.cnr.it
Esposito
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D000818:Animals; D005075:Biological Evolution; D002520:Cercopithecidae; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D004198:Disease Susceptibility; D006801:Humans; D007669:Kidney Calculi / Q000737:chemistry* / Q000235:genetics*; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics*; D014527:Uric Acid / Q000378:metabolism*
D014527:Uric Acid