Alternative titles; symbols
HGNC Approved Gene Symbol: AGXT
SNOMEDCT: 65520001;
Cytogenetic location: 2q37.3 Genomic coordinates (GRCh38) : 2:240,868,824-240,880,500 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.3 | Hyperoxaluria, primary, type 1 | 259900 | Autosomal recessive | 3 |
The AGXT gene encodes alanine:glyoxylate aminotransferase (AGT; EC 2.6.1.44), whose activity is largely confined to peroxisomes in the liver. AGT also shows serine:pyruvate aminotransferase activity (EC 2.6.1.51) (Noguchi et al., 1978).
Takada et al. (1990) isolated clones corresponding to the AGT gene from a human liver cDNA library. The deduced 392-residue protein had a calculated molecular mass of 43 kD. The human peroxisomal AGT showed about 78% amino acid sequence identity with rat mitochondrial AGT. The putative pyridoxal phosphate-binding lysine residue at position 209 is conserved. A comparison of the 5-prime sequences indicated that the N-terminal 22 amino acids of the rat translation product are absent from the human protein. The loss of this mitochondrial targeting sequence (MTS) signal during evolution may partly explain the species differences in intracellular localization of AGT.
Purdue et al. (1990) isolated a clone encoding human liver-specific peroxisomal AGT, also called AGXT. The nucleotide sequences corresponded to the sequence of the AGT cDNA characterized by Takada et al. (1990). The results of genomic Southern blotting indicated that the human AGT gene is a probably single copy.
Cellini et al. (2009) noted that AGT functions as a dimer, and each AGT monomer consists of an N-terminal arm involved in dimer formation, a large catalytic domain containing an active site lys209, and a smaller C-terminal domain. One pyridoxal 5-prime-phosphate (PLP) cofactor binds per subunit and is present in a Schiff base linkage with lys209.
Purdue et al. (1990) determined that the coding sequence of the AGXT gene spans 10 kb and contains 11 exons.
By in situ hybridization and PCR analysis of rodent/human somatic cell hybrids, Purdue et al. (1991) mapped the AGXT gene to chromosome 2q36-q37.
Mori et al. (1992) showed by in situ hybridization that a single gene for this enzyme in the rat, symbolized SPT/AGT, is located on chromosome 9q34-q36.
Primary hyperoxaluria type 1 (259900) is an autosomal recessive disorder caused by deficiency of alanine:glyoxylate aminotransferase (AGT), characterized by progressive kidney failure due to renal deposition of calcium oxalate. In about one-third of patients residual enzyme activity is up to 60% of mean normal, but in most of these patients AGT is mistargeted to mitochondria instead of peroxisomes. The mistargeting mutation gly170-to-arg (G170R; 604285.0013) is the most common mutation among Caucasian patients, with a frequency of 23 to 27%. The G170R mutation always occurs on the background of the minor allele (see 604285.0002), with which it interacts synergistically (summary by Coulter-Mackie and Rumsby, 2004).
Danpure and Jennings (1986) demonstrated that total AGXT levels were reduced in 2 patients with type I primary hyperoxaluria (259900).
In a patient with primary hyperoxaluria type I (HP1; 259900), Nishiyama et al. (1991) identified a mutation in the AGXT gene (S205P; 604285.0001). SPT activity was approximately 1% of that in control liver.
The intermediary metabolic enzyme AGT contains a pro11-to-leu (P11L; 604285.0002) polymorphism that decreases its catalytic activity by a factor of 3 and causes a small proportion to be mistargeted from its normal intracellular location in the peroxisomes to the mitochondria. These changes were predicted to have significant effects on the synthesis and excretion of the metabolic end-product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract (summary by Danpure, 1997).
In 15 unrelated Italian patients with type I primary hyperoxaluria, Pirulli et al. (1999) 8 novel mutations in the AGXT gene (see, e.g., G158R, 604285.0012). The most frequent mutation was G170R (604285.0013), accounting for 30% of alleles, followed by G158R, with a 13% frequency. Ten of the 15 patients were homozygotes; in only 1 case were the parents identified as first cousins.
In a mutation update of the AGXT gene, Williams et al. (2009) stated that 146 mutations had been identified, with all exons of the AGXT gene represented. The authors identified 50 novel mutations in patients with HP1. There were no apparent genotype/phenotype correlations.
Fargue et al. (2013) showed that 3 disease-causing missense mutations, I244T (604285.0007), F152I (604285.0006), and G41R (604285.0005), which occur on the background of the minor allele characterized by the P11L polymorphism, can, like G170R, unmask the cryptic P11L-generated mitochondrial targeting sequence and result in AGT protein being mistargeted to mitochondria. These 4 missense mutations together constitute 40% of HP1 alleles.
Based on the evolution of AGT targeting in mammals, Danpure (1997) hypothesized that the common P11L polymorphism would be advantageous for individuals who have a meat-rich diet, but disadvantageous for those who do not. If true, the frequency of distribution of P11L in different extant human populations should have been shaped by their dietary history so that it should be more common in populations with predominantly meat-eating ancestral diets than it is in populations in which the ancestral diet was predominantly vegetarian. In a study of frequency of P11L in 11 different human populations with divergent ancestral dietary lifestyles, Caldwell et al. (2004) found evidence in support of the hypothesis: the highest allelic frequency, 27.9%, was found in the Saami, a population with a very meat-rich ancestral diet; the lowest, 2.3%, was found in Chinese, who were likely to have had a more mixed ancestral diet. The differences in P11L frequency between some populations (particularly Saami vs Chinese) was very high when compared with neutral loci, suggesting that its frequency might have been shaped by dietary selection pressure.
Fargue et al. (2013) stated that the minor allele characterized by the P11L polymorphism occurs in 15 to 20% of European and North American populations.
Salido et al. (2006) found that Agt1-null mice grew and developed normally; however they developed hyperoxaluria and crystalluria. About half of the male mice in mixed genetic background developed calcium oxalate urinary stones. Severe nephrocalcinosis and renal failure developed after pharmacologic enhancement of oxalate production. Hepatic expression of human AGT1 by adenoviral vector-mediated gene transfer in Agt1 -/- mice normalized urinary oxalate excretion and prevented oxalate crystalluria. Subcellular fractionation and immunofluorescence studies revealed that, as in the human liver, the expression of transgenic AGT1 was predominantly localized to hepatocellular peroxisomes.
Nishiyama et al. (1991) obtained cDNA clones for serine:pyruvate aminotransferase from a cDNA library constructed from the liver of a patient with primary hyperoxaluria type I (HP1; 259900) in which the SPT activity was approximately 1% of that in control liver. Genetic analysis identified a 634T-C transition in the AGXT gene, resulting in a ser205-to-pro (S205P) substitution. The T-to-C conversion created a new SmaI site.
This variant, formerly titled HYPEROXALURIA, PRIMARY, TYPE I, has been reclassified as a polymorphism.
The pro11-to-leu substitution (P11L) is the primary polymorphism that defines the minor allele of AGXT that occurs with an allele frequency of 15 to 20% in European and North American populations and 50% of patients with primary hyperoxaluria type I (HP1; 259900). The absence of these polymorphisms defines the major allele. The P11L replacement creates a hidden N-terminal mitochondrial targeting sequence that can be unmasked by additional amino acid substitutions in cis, resulting in disease (summary by Fargue et al., 2013).
Coulter-Mackie and Rumsby (2004) noted that the P11L substitution results from a 32C-T transition in exon 1 of AGXT.
Purdue et al. (1990) found that approximately one-third of patients with type I primary hyperoxaluria have an allele carrying 3 point mutations, each of which specifies a single amino acid substitution: P11L, gly170-to-arg (G170R; 604285.0013), and ile340-to-met (I340M; 604285.0014). A minority of such patients are homozygous for this allele; most appear to be heterozygous, i.e., compound heterozygotes. The G170R substitution was not found in controls; however, the other 2 mutations cosegregated in the normal population at an allelic frequency of 5 to 10%. Studies suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import.
Purdue et al. (1991) showed that the P11L variant is necessary and sufficient for the generation of a mitochondrial targeting sequence (MTS) in the AGT protein. The N-terminal 19 amino acids of AGT with this substitution were sufficient to direct mouse cytosolic dihydrofolate reductase to mitochondria. Although the P11L mutation creates an MTS, the G170R mutation appeared to be necessary for redirection of AGT to the mitochondria, presumably by interfering with the mechanism of targeting to peroxisomes. Purdue et al. (1991) also studied the region of normal human AGT cDNA directly upstream of the coding region. They found that this sequence appears to correspond to an ancestral MTS deleted from the human coding region by a point mutation at the initiation codon. The reestablishment of this initiation codon produced an active MTS that was different from that observed in hyperoxaluria patients. The protein sorting defect found in approximately one-third of patients with primary hyperoxaluria type I is unique. The subcellular distribution of AGT is species-specific. The rat, for example, is one of a number of species in which AGT is a naturally occurring mitochondrial protein. In human AGT cDNA, the region homologous to that encoding the rat AGT MTS lies within the 5-prime untranslated region, being excluded from the open reading frame due to a coding difference (ATG in rat, ATA in human) at the rat-equivalent translation initiation site. The evolutionary loss of this ATG codon appears to explain the exclusive peroxisomal localization of human AGT; reestablishment of this codon could represent another mechanism for mitochondrial mistargeting of AGT in humans. Whereas humans, rabbits, and guinea pigs do not target AGT to the mitochondrion, rats, cats, and marmosets are among those species that do.
Salido et al. (2006) showed that transgenic mice predominantly expressed wildtype human AGT1 in hepatocellular peroxisomes, whereas AGT1 with the G170R mutation localized to mitochondria.
The P11L and G170R variants occur with other AGXT polymorphisms on the minor allele haplotype, which is population-dependent. The frequency of this minor allele haplotype is 10 to 20% in Caucasians, but only 2% in Japanese. In primary hyperoxaluria type I, the frequency is about 46% (Williams et al., 2009).
Using recombinant epitope-tagged proteins expressed in E. coli, Lumb and Danpure (2000) determined the effects of the most common normal and disease-causing substitutions on the properties of AGT. Recombinant AGT expressed from the major allele was functionally similar to human liver AGT in binding alanine, glyoxylate, and pyridoxal phosphate in pH optima and in the ability to dimerize. However, recombinant AGT carrying the P11L and I340M variants (AGT(L11,M340)) associated with the minor allele had only 46 to 50% of the wildtype alanine:glyoxylate aminotransferase activity. The lower specific activity of the AGT(L11,M340) appeared to be entirely due to the presence of the P11L polymorphism rather than the I340M polymorphism, since the activity of AGT(L11) was about 25% of wildtype, and the activity of AGT(M340) was comparable or higher wildtype. Other mutations that segregate almost exclusively with the minor allele, G41R (604285.0005), F152I (604285.0006), and I244T (604285.0007), are associated with absence or near absence of immunoreactive AGT protein and catalytic activity. When AGT(R41) was expressed alone on the background of the major AGT allele, it showed 7% residual activity; however, the other substitutions showed between 44 and 59% residual activity and were predicted to be innocuous in the absence of P11L. The G170R substitution that segregates with the minor allele causes the mistargeting of AGT to mitochondria.
Purdue et al. (1991) identified a 74-bp duplication within the first intron of the AGXT gene and showed that the duplication is closely linked to 2 point mutations associated with the peroxisome-to-mitochondrion mistargeting. They showed that the duplication is useful in identifying hyperoxaluria (259900) patients with so-called mAGT (i.e., mitochondrial AGT) and also facilitates the identification of additional mutations in the non-mAGT allele of compound heterozygotes with mAGT. They illustrated this fact by identification of a tyr66-to-ter (Y66X) mutation resulting from a C-to-G change in exon 2.
Purdue et al. (1992) found a G-to-A transition at nucleotide 367 of the AGXT cDNA, which was predicted to cause a glycine-to-glutamate substitution at residue 82 (G82Q) of the AGT protein. The mutation was located in exon 2 and led to the loss of an AvaI restriction site. The patient was homozygous. The same mutation was found in homozygous state in 1 related and 2 unrelated patients with type I primary hyperoxaluria (259900). One other phenotypically similar patient lacked the mutation, however.
Lumb and Danpure (2000) noted that AGT carrying the G82E substitution does not affect the stability or mitochondria targeting of AGT, but eliminates its catalytic activity. Using recombinant proteins expressed in E. coli, they showed that AGT with this substitution did not bind the pyridoxal phosphate cofactor.
Danpure et al. (1993) observed 2 patients with hyperoxaluria (259900) who were compound heterozygotes for 2 previously unrecognized point mutations that caused gly41-to-arg (G41R) and phe152-to-ile (604285.0006) amino acid substitutions. Both were homozygous for the pro11-to-leu polymorphism that had previously been found with a high allelic frequency in the normal populations. They suggested that the phe152-to-ile substitution, which is located in a 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-to-leu polymorphism, be responsible for its aberrant mitochondrial compartmentalization. The gly41-to-arg substitution, either in combination with the pro11-to-leu polymorphism or by itself, was predicted to be responsible for the intraperoxisomal aggregation of AGT protein. Unlike normal individuals in whom the AGT is confined to the peroxisomal matrix, the immunoreactive AGT in these 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. They presented electromicrographic views of the peroxisomal cores.
Using recombinant epitope-tagged proteins expressed in E. coli, Lumb and Danpure (2000) determined the effects of the most common normal and disease-causing substitutions on the properties of AGT. They found that when the G41R mutation (AGT(R41)) was expressed alone on the background of the major AGT allele, it showed 7% residual activity.
By expressing the major allele of AGT carrying the G41R substitution in E. coli, Cellini et al. (2009) showed that the G41R substitution resulted in significantly reduced AGT activity that was independent of the P11L substitution. The G41R substitution alone resulted in about 7% residual activity.
Fargue et al. (2013) found that the G41R mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. They also found that whereas the other missense mutations they tested were able to form dimers and were catalytically active, the G41R mutant aggregates and is inactive.
See 604285.0005 and Danpure et al. (1993).
AGT exists as 2 polymorphic variants, a major allele (AGT-Ma) and a minor allele (AGT-Mi) (see 604285.0002), which shows lower AGT activity compared with AGT-Ma. AGT-Mi also causes PH1 only when combined with specific mutations, including F152I. Cellini et al. (2009) showed that the F152I substitution does not affect the transaminase activity of AGT-Mi, but plays a role in stabilizing the aminated cofactor, pyridoxamine 5-prime-phosphate (PMP) produced during the L-alanine half-transamination reaction. The F152I substitution in both AGT-Mi and AGT-Ma caused the premature release of PMP, resulting in the formation of the apoenzyme in both isoforms. In the context of AGT-Mi, however, F152I additionally causes destabilization of the enzyme at physiologic temperatures, with concomitant protein aggregation and loss of enzyme activity.
Fargue et al. (2013) found that the F152I mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria.
One of the mutations clustered in exon 7 of the AGXT gene identified by von Schnakenburg and Rumsby (1997) in studies of 79 patients with type I primary hyperoxaluria (PH1; 259900) was an 853T-C transition that led to a predicted ile244-to-thr (I244T) substitution. This was found in homozygous or heterozygous state in 9% of patients, making it the second most common mutation found up to that time.
Santana et al. (2003) reported that most of the AGXT alleles detected in patients from the Canary Islands with PH1 carry the I244T mutation; 14 of 16 patients they studied were homozygous for this mutation and shared in their haplotypes 4 polymorphisms within AGXT and regional microsatellites (AGXT*LTM), consistent with a founder effect. Santana et al. (2003) investigated the consequence of these amino acid changes and found that although I244T alone did not affect AGXT activity or subcellular localization (i.e., mitochondria vs peroxisomes), when present in the same protein molecule as L11P (see 604285.0002), it resulted in loss of enzymatic activity in soluble cell extracts. Like its normal counterpart, the AGXT*LTM protein was present in the peroxisomes but was insoluble in detergent-free buffers. The L11P polymorphism behaved as an intragenic modifier of the I244T mutation, with the resulting protein undergoing stable interaction with molecular chaperones and temperature-sensitive aggregation. Among various chemical chaperones tested in cell culture, betaine substantially improved the solubility of the mutant protein and the enzymatic activity in cell lysates. Santana et al. (2003) concluded that the synergistic effect of P11L with I244T causes PH1, a protein conformational disease.
Fargue et al. (2013) found that the I244T mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria.
In a patient with type I primary hyperoxaluria (259900), von Schnakenburg and Rumsby (1997) found a homozygous 819C-T transition in the AGXT gene that mutated codon 233 from arginine to cysteine (R233C). A mutation in the adjacent nucleotide, 820G-A, mutated the same codon from arginine to histidine (604285.0009).
See 604285.0008 and von Schnakenburg and Rumsby (1997).
In a patient with type I primary hyperoxaluria (259900), von Schnakenburg and Rumsby (1997) found heterozygosity for an 860G-A transition in exon 7 of the AGXT gene, introducing a stop codon at amino acid residue 246.
In a study of 15 unrelated Italian patients with type I primary hyperoxaluria (259900), Pirulli et al. (1999) found that the second most frequent AGXT allele carried a gly158-to-arg (G158R) mutation, with a prevalence of 13%. The mutation resulted from a 588G-A transition.
Coulter-Mackie and Rumsby (2004) noted that the gly170-to-arg (G170R) mutation results from a 508G-A (with position 1 being the first coding nucleotide) transition in exon 4 of AGXT.
Purdue et al. (1990) found that approximately one-third of patients with type I primary hyperoxaluria have an allele carrying 3 point mutations, each of which specifies a single amino acid substitution: pro11-to-leu (P11L; 604285.0002), G170R, and ile340-to-met (I340M; 604285.0014). A minority of such patients are homozygous for this allele; most appear to be heterozygous, i.e., compound heterozygotes. The G170R substitution was not found in controls; however, the other 2 mutations cosegregated in the normal population at an allelic frequency of 5 to 10%. Studies suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import.
Purdue et al. (1991) showed that although the P11L mutation creates a mitochondrial targeting sequence (MTS), the G170R mutation appeared to be necessary for redirection of AGT to the mitochondria, presumably by interfering with the mechanism of targeting to peroxisomes.
Salido et al. (2006) showed that transgenic mice predominantly expressed wildtype human AGT1 in hepatocellular peroxisomes, whereas AGT1 with the G170R mutation localized to mitochondria.
In a study of 15 unrelated Italian patients with type I primary hyperoxaluria, Pirulli et al. (1999) found that the most frequent AGXT allele carried the G170R mutation, with a prevalence of 30%. The mutation results from a 630G-A transition. The mutation was found on the background of the minor allele.
Lumb and Danpure (2000) found that the G170R substitution that segregates with the minor allele causes the mistargeting of AGT to mitochondria.
This variant, formerly titled HYPEROXALURIA, PRIMARY, TYPE I, has been reclassified as a polymorphism.
Coulter-Mackie and Rumsby (2004) noted that the ile340-to-met (I340M) substitution results from a 1020A-G transition exon 10 of AGXT.
Lumb and Danpure (2000) found that recombinant AGT carrying the P11L (604285.0002) and I340M variants (AGT(L11,M340)) associated with the minor allele had only 46 to 50% of the wildtype alanine:glyoxylate aminotransferase activity. The lower specific activity of the AGT(L11,M340) appeared to be entirely due to the presence of the P11L polymorphism rather than the I340M polymorphism, since the activity of AGT(L11) was about 25% of wildtype, and the activity of AGT(M340) was comparable or higher wildtype.
Coulter-Mackie and Rumsby (2004) stated that the 33_34insC mutation in exon 1 of the AGXT gene, which occurs on the background of the major allele, is found at a frequency of 12% in affected individuals.
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