Cj. Danpure et al., ENZYMOLOGICAL AND MUTATIONAL ANALYSIS OF A COMPLEX PRIMARY HYPEROXALURIA TYPE-1 PHENOTYPE INVOLVING ALANINE - GLYOXYLATE AMINOTRANSFERASE PEROXISOME-TO-MITOCHONDRION MISTARGETING AND INTRAPEROXISOMAL AGGREGATION, American journal of human genetics, 53(2), 1993, pp. 417-432
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disea
se caused by a deficiency of the liver-specific peroxisomal enzyme ala
nine:glyoxylate aminotransferase (AGT). Three unrelated PH1 patients,
who possess a novel complex phenotype, are described. At the enzymolog
ical level, this phenotype is characterized by a complete, or nearly c
omplete, absence of AGT catalytic activity and reduced AGT immunoreact
ivity. Unlike normal individuals in whom the AGT is confined to the pe
roxisomal matrix, the immunoreactive AGT in these three patients was d
istributed approximately equally between the peroxisomes and mitochond
ria. The peroxisomal AGT appeared to be aggregated into amorphous core
-like structures in which no other peroxisomal enzymes could be identi
fied. 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 s
ubstitutions. The third patient was shown to be a compound heterozygot
e for the Gly41-->Arg mutation and a previously recognized Gly170-->Ar
g mutation. All three patients were homozygous for the Pro11-->Leu pol
ymorphism that had been found previously with a high allelic frequency
in normal populations. It is suggested that the Phe152-->Iso and Gly1
70-->Arg substitutions, which are only eighteen residues apart and loc
ated in the same highly conserved internal region of 58 amino acids, m
ight be involved in the inhibition of peroxisomal targeting and/or imp
ort of AGT and, in combination with the Pro11-->Leu polymorphism, be r
esponsible 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 responsi
ble for the intraperoxisomal aggregation of the AGT protein.