Publications

Authors:

Jose M., Sanchez Ruiz; Melissa D., Lage; Adrianne M. C., Pittman; Roncador, Alessandro; Cellini, Barbara; Chandra L., Tucker

Title:

Allele-specific Characterization of Alanine: Glyoxylate Aminotransferase Variants Associated with Primary Hyperoxaluria

Year:

2014

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

Sì

Name of journal:

PLoS ONE

ISSN of journal:

1932-6203

N° Volume:

9

Page numbers:

e94338-e94338

Keyword:

Primary hyperoxaluria type 1; alanine:glyoxylate aminotransferase; Enzymatic activities

Short description of contents:

Primary Hyperoxaluria Type 1 (PH1) 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 PH1. 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 PH1. 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 PH1-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, E274D, that appears to specifically affect activity when in combination with the minor allele.

Product ID:

81064

Handle IRIS:

11562/717567

Deposited On:

May 2, 2014

Last Modified:

November 15, 2022

Bibliographic citation:

Jose M., Sanchez Ruiz; Melissa D., Lage; Adrianne M. C., Pittman; Roncador, Alessandro; Cellini, Barbara; Chandra L., Tucker, Allele-specific Characterization of Alanine: Glyoxylate Aminotransferase Variants Associated with Primary Hyperoxaluria «PLoS ONE» , vol. 9 , 2014 , pp. e94338-e94338

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