Allele-specific characterization of alanine: glyoxylate aminotransferase variants associated with primary hyperoxaluria.

[primary hyperoxaluria type 1]

Primary Hyperoxaluria Type 1 (PH 1 ) is a rare autosomal recessive kidney stone disease caused by deficiency of the peroxisomal enzyme alanine : glyoxylate aminotransferase (AGT ), which is involved in glyoxylate detoxification . Over 75 different missense mutations in AGT have been found associated with PH 1 . While some of the mutations have been found to affect enzyme activity , stability , and /or localization , approximately half of these mutations are completely uncharacterized . In this study , we sought to systematically characterize AGT missense mutations associated with PH 1 . To facilitate analysis , we used two high -throughput yeast-based assays : one that assesses AGT specific activity , and one that assesses protein stability . Approximately 30 % of PH 1 -associated missense mutations are found in conjunction with a minor allele polymorphic variant , which can interact to elicit complex effects on protein stability and trafficking . To better understand this allele interaction , we functionally characterized each of 34 mutants on both the major (wild-type ) and minor allele backgrounds , identifying mutations that synergize with the minor allele . We classify these mutants into four distinct categories depending on activity /stability results in the different alleles . Twelve mutants were found to display reduced activity in combination with the minor allele , compared with the major allele background . When mapped on the AGT dimer structure , these mutants reveal localized regions of the protein that appear particularly sensitive to interactions with the minor allele variant . While the majority of the deleterious effects on activity in the minor allele can be attributed to synergistic interaction affecting protein stability , we identify one mutation , E 274 D , that appears to specifically affect activity when in combination with the minor allele .

Diseases
Validation

Diseases presenting "specific activity" symptom

erythropoietic protoporphyria

primary hyperoxaluria type 1

pyruvate dehydrogenase deficiency

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