Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). Three unrelated PH1 patients, who possess a novel complex phenotype, are described. At the enzymological level, this phenotype is characterized by a complete, or nearly complete, absence of AGT catalytic activity and reduced AGT immunoreactivity. Unlike normal individuals in whom the AGT is confined to the peroxisomal matrix, the immunoreactive AGT in these three patients was distributed approximately equally between the peroxisomes and mitochondria. The peroxisomal AGT appeared to be aggregated into amorphous core-like structures in which no other peroxisomal enzymes could be identified. Mutational analysis of the AGT gene showed that two of the three patients were compound heterozygotes for two previously unrecognized point mutations which caused Gly41 → Arg and Phe152 → Iso amino acid substitutions. The third patient was shown to be a compound heterozygote for the Gly41 → Arg mutation and a previously recognized Gly170 → Arg mutation. All three patients were homozygous for the Pro11 → Leu polymorphism that had been found previously with a high allelic frequency in normal populations. It is suggested that the Phe152 → Iso and Gly170 → Arg substitutions, which are only eighteen residues apart and located in the same highly conserved internal region of 58 amino acids, might be involved in the inhibition of peroxisomal targeting and/or import of AGT and, in combination with the Pro11 → Leu polymorphism, be responsible for its aberrant mitochondrial compartmentalization. On the other hand, the Gly41 → Arg substitution, either in combination with the Pro11 → Leu polymorphism or by itself, is predicted to be responsible for the intraperoxisomal aggregation of the AGT protein.
|Original language||English (US)|
|Number of pages||16|
|Journal||American Journal of Human Genetics|
|State||Published - 1993|