PRIMARY HYPEROXALURIA TYPE-1 - GENOTYPIC AND PHENOTYPIC HETEROGENEITY

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease c aused by a deficiency of the liver-specific peroxisomal enzyme alanine : glyoxylate aminotransferase (AGT). The disease is notable for its ex tensive heterogeneity at the clinical, biochemical, enzymic and molecu lar genetic levels. A study of 116 PH1 patients over the past 8 years has revealed four main enzymic phenotypes: (1) absence of both AGT cat alytic activity and immunoreactive AGT protein (similar to 40% of pati ents); (2) absence of AGT catalytic activity but presence of immunorea ctive protein (similar to 16% of patients); (3) presence of both AGT c atalytic activity and immunoreactive protein (similar to 41% of patien ts), in most of which cases the AGT is mistargeted to the mitochondria instead of the peroxisomes; and (4) a variation of the mistargeting p henotype in which AGT is equally distributed between peroxisomes and m itochondria, but in which that in the peroxisomes is aggregated into m atrical core-like structures (similar to 3% of patients). Various poin t mutations, all occurring at conserved positions in the coding region s of the AGT gene, have been identified in these patients. The five mu tations discussed in the present study, which have been found in indiv iduals manifesting all of the four major enzymic phenotypes, account f or the expressed alleles in about half of all Caucasian PH1 patients. The most common mutation found so far leads to a Gly170 --> Arg amino acid substitution. This mutation, in combination with a normally occur ring Pro 11 --> Leu polymorphism, appears to be responsible for the un precedented peroxisome-to-mitochondrion mistargeting phenotype.