AGXT – Primary Hyperoxaluria Type 1

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive metabolic disorder caused by pathogenic variants in AGXT (alanine:glyoxylate aminotransferase) leading to hepatic enzyme deficiency, excessive oxalate production, and progressive renal failure ([PMID:24988064]). Patients present with recurrent nephrolithiasis and nephrocalcinosis (HP:0000787; HP:0000121), often culminating in end-stage kidney disease in childhood or early adulthood.

Genetic evidence for the AGXT–PH1 association is definitive. Over 600 unrelated probands from >50 families have been reported with biallelic AGXT variants ([PMID:24988064]; [PMID:35812297]). The variant spectrum includes >80 missense, >20 splicing, and >30 truncating mutations, with recurrent alleles such as c.508G>A (p.Gly170Arg) and c.731T>C (p.Ile244Thr) accounting for significant fractions of cases ([PMID:24988064]). Segregation analysis in multiple pedigrees demonstrates co-segregation of AGXT mutations with disease in affected siblings and extended relatives (n = 2 affected cousins) ([PMID:10737993]).

Case reports and series confirm autosomal recessive inheritance, with most patients compound heterozygous or homozygous for AGXT loss-of-function alleles. Representative variant: c.508G>A (p.Gly170Arg) occurs in both infantile and adult-onset presentations and disrupts enzyme activity ([PMID:20056599]).

Functional studies elucidate a haploinsufficiency and protein misfolding mechanism. Common missense mutations reduce AGT specific activity to <10% of wild-type and cause peroxisomal mistargeting or aggregation ([PMID:20056599]; [PMID:36682331]). Structural analyses of AGXT–GroEL complexes reveal non-native folding intermediates, and cryo-EM demonstrates chaperonin-mediated unfolding of mutant AGT ([PMID:20056599]).

Pyridoxine (vitamin B6) acts as a pharmacological chaperone for responsive genotypes. Homozygous p.Gly170Arg patients exhibit pyridoxine-correctable mistargeting and maintain stable graft function after kidney-alone transplantation ([PMID:12777626]; [PMID:24797341]). However, non-responsive alleles require combined liver-kidney transplantation for definitive cure.

No credible studies dispute the AGXT–PH1 relationship. Diagnostic genetic testing of AGXT now supplants invasive liver biopsies in most settings. Early molecular diagnosis allows genotype-guided therapy and family counseling.

Key Take-home: AGXT pathogenic variants cause definitive autosomal recessive PH1, with comprehensive genetic and functional evidence supporting targeted therapies and genetic testing for early diagnosis and management.

References

• Kidney international • 2014 • Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type PMID:24988064
• Molecular genetics and metabolism • 2006 • Consequences of missense mutations for dimerization and turnover of alanine:glyoxylate aminotransferase: study of a spectrum of mutations PMID:16971151
• Proceedings of the National Academy of Sciences • 2003 • Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase PMID:12777626
• Biochemical and biophysical research communications • 2023 • Biochemical and cellular effects of a novel missense mutation of the AGXT gene associated with Primary Hyperoxaluria Type 1 PMID:36682331

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