Enzymological and mutational analysis of a complex primary hyperoxaluria type I phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation

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 phe...

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Bibliographic Details
Published in:American journal of human genetics 1993, Vol.53 (2), p.417-432
Main Authors: Danpure, C J, Purdue, P E, Fryer, P, Griffiths, S, Allsop, J, Lumb, MJ, Guttridge, K M, Jennings, PR, Davidson, N O
Format: Article
Language:English
Subjects:
550900 > Pathology
aggregation
alanine-glyoxylate transaminase
AMINOTRANSFERASES
BASIC BIOLOGICAL SCIENCES
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BODY
BODY FLUIDS
CARBOXYLIC ACIDS
CELL CONSTITUENTS
DICARBOXYLIC ACIDS
DIGESTIVE SYSTEM
DISEASES
ENZYMES
GENE MUTATIONS
GLANDS
GLYCOLIC ACID
HYDROXY ACIDS
hyperoxaluria
KIDNEYS
LIVER
man
MATERIALS
METABOLIC DISEASES
MITOCHONDRIA
MONOCARBOXYLIC ACIDS
mutation
MUTATIONS
NITROGEN TRANSFERASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXALIC ACID
peroxisomes
phenotypes
PROTEINS
RFLPS
targeting
TRANSFERASES
URINE
WASTES 550400 > Genetics
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Description
Summary: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 arrow right Arg and Phe152 arrow right Iso amino acid substitutions. The third patient was shown to be a compound heterozygote for the Gly41 arrow right Arg mutation and a previously recognized Gly170 arrow right Arg mutation. All three patients were homozygous for the Pro11 arrow right Leu polymorphism that had been found previously with a high allelic frequency in normal populations. It is suggested that the Phe152 arrow right Iso and Gly170 arrow right 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 arrow right Leu polymorphism, be responsible for its aberrant mitochondrial compartmentalization. On the other hand, the Gly41 arrow right Arg substitution, either in combination with the Pro11 arrow right Leu polymorphism or by itself, is predicted to be responsible for the intraperoxisomal aggregation of the AGT protein.
ISSN:0002-9297
1537-6605