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Primary Hyperoxaluria Type I

A Model for Multiple Mutations in aMonogenic Disease within a Distinct Ethnic Group

CHONI RINAT^*, RONALD J. A. WANDERS, ALFRED DRUKKER^*, DAVID HALLE^* and YAACOV FRISHBERG^*

^* Division of Pediatric Nephrology, Shaare Zedek Medical Center and Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands

Correspondence to Dr. Yaacov Frishberg, Division of Pediatric Nephrology, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel. Phone: +972 2 6666144; Fax: +972 2 6513946; E-mail: yaacov{at}md2.huji.ac.il

Abstract. Primary hyperoxaluria type 1 is an autosomal recessive inherited metabolic disease in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of phenotypes ranging from renal failure in infancy to mere renal stones in late adulthood. Mutations in the AGXT gene, encoding the liver-specific enzyme alanine:glyoxylate aminotransferase, are responsible for the disease. Seven mutations were detected in eight families in Israel. Four of these mutations are novel and three occur in children living in single-clan villages. The mutations are scattered along various exons (1, 4, 5, 7, 9, 10), and on different alleles comprissing at least five different haplotypes. All but one of the mutations are in a homozygous pattern, reflecting the high rate of consanguinity in our patient population. Two affected brothers are homozygous for two different mutations expressed on the same allele. The patients comprise a distinct ethnic group (Israeli Arabs) residing in a confined geographic area. These results, which are supported by previous data, suggest for the first time that the phenomenon of multiple mutations in a relatively closed isolate is common and almost exclusive to the Israeli-Arab population. Potential mechanisms including selective advantage to heterozygotes, digenic inheritance, and the recent emergence of multiple mutations are discussed.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673