Primary hyperoxaluria type 1 in the Canary Islands: A conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase

• DOI: 10.1073/pnas.1131968100
• Publication Date: 2003-06-10T17:06:36Z
• Authors: A. Santana; E. Salido; A. Torres; L. J. Shapiro
• Keywords: Primary hyperoxaluria; Alanine; Chemical chaperone; Mutant protein

Primary hyperoxaluria type 1 (PH1) is an inborn error of metabolism resulting from a deficiency alanine:glyoxylate aminotransferase (AGXT; EC 2.6.1.44). Most the PH1 alleles detected in Canary Islands carry Ile-244 → Thr (I244T) mutation AGXT gene, with 14 16 patients homozygous for this mutation. Four polymorphisms within and regional microsatellites also were shared their haplotypes ( * LTM ), consistent founder effect. The consequences these amino acid changes investigated. Although I244T alone did not affect activity or subcellular localization, when present same protein molecule as Leu-11 Pro (L11P), it resulted loss enzymatic soluble cell extracts. Like its normal counterpart, was peroxisomes but insoluble detergent-free buffers. polymorphism L11P behaved intragenic modifier mutation, undergoing stable interaction molecular chaperones aggregation. This aggregation temperature-sensitive. expressed Escherichia coli , GST-fusion protein, insect cells could be purified retained activity. Among various chemical tested culture, betaine substantially improved solubility mutant lysates. In summary, I244T, second most common responsible PH1, conformational disease that may benefit new therapies pharmacological small molecules to minimize