Primary hyperoxaluria type 1: Genotypic and phenotypic heterogeneity

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Abstract
Summary: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by a deficiency of the liver‐specific peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT). The disease is notable for its extensive heterogeneity at the clinical, biochemical, enzymic and molecular genetic levels. A study of 116 PH1 patients over the past 8 years has revealed four main enzymic phenotypes: (1) absence of both AGT catalytic activity and immunoreactive AGT protein (≈40% of patients); (2) absence of AGT catalytic activity but presence of immunoreactive protein (≈16% of patients); (3) presence of both AGT catalytic activity and immunoreactive protein (≈41% of patients), in most of which cases the AGT is mistargeted to the mitochondria instead of the peroxisomes; and (4) a variation of the mistargeting phenotype in which AGT is equally distributed between peroxisomes and mitochondria, but in which that in the peroxisomes is aggregated into matrical core‐like structures (≈3% of patients). Various point mutations, all occurring at conserved positions in the coding regions of the AGT gene, have been identified in these patients. The five mutations discussed in the present study, which have been found in individuals manifesting all of the four major enzymic phenotypes, account for 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 occurring Pro11 → Leu polymorphism, appears to be responsible for the unprecedented peroxisome‐to‐mitochondrion mistargeting phenotype.