Primary hyperoxaluria type I: A model for multiple mutations in a monogenic disease within a distinct ethnic group

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 fail ure in infancy to mere renal stones in late adulthood. Mutations in the AGX T gene, encoding the liver-specific enzyme alanine:glyoxylate aminotransfer ase, are responsible for the disease. Seven mutations were detected in eigh t families in Israel. Four of these mutations are novel and three occur in children Living in single-dan villages. The mutations are scattered along v arious exons (1, 4, 5, 7, 9, 10), and on different alleles comprising at le ast five different haplotypes. Ail but one of the mutations are in a homozy gous pattern, reflecting the high rate of consanguinity in our patient popu lation. Two affected brothers are homozygous for two different mutations ex pressed 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 phenom enon of multiple mutations in a relatively closed isolate is common and alm ost exclusive to the Israeli-Arab population. Potential mechanisms includin g selective advantage to heterozygotes, digenic inheritance, and the recent emergence of multiple mutations are discussed.