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Structural analysis of clinically relevant pathogenic G6PD variants reveals the importance of tetramerization for G6PD activity.

ABSTRACT: Over 220 different amino acid variants have been identified in human glucose-6-phosphate dehydrogenase (G6PD), covering over 30% of the protein sequence. Many of these variants are pathogenic, causing varying degrees of G6PD deficiency with symptoms ranging from severe chronic anemia (class I) to milder triggered hemolytic episodes (classes II and III). The phenotypic effects of most G6PD variants have been reported, providing an opportunity to correlate phenotypic and structural information. In particular, we sought to investigate the tetramer interface of G6PD in relation to pathogenic variation, as there are conflicting reports indicating the importance of tetramerization for G6PD activity. Using a three-dimensional spatial scan statistic, hotspots of structural enrichment were identified for each class of pathogenic G6PD variants. Class I variants, the most phenotypically severe, were enriched at the dimer interface, consistent with previous evidence that dimerization is essential for G6PD activity. Class II variants were enriched near the tetramer interface, suggesting that tetramerization is also important for G6PD activity. This analysis explains why these two classes, both yielding 10% or less G6PD activity as compared to normal, lead to different clinical outcomes.

SUBMITTER: Cunningham AD

PROVIDER: S-EPMC6105287 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Structural analysis of clinically relevant pathogenic G6PD variants reveals the importance of tetramerization for G6PD activity.

Cunningham Anna D AD Mochly-Rosen Daria D

Matters 20170901

Over 220 different amino acid variants have been identified in human glucose-6-phosphate dehydrogenase (G6PD), covering over 30% of the protein sequence. Many of these variants are pathogenic, causing varying degrees of G6PD deficiency with symptoms ranging from severe chronic anemia (class I) to milder triggered hemolytic episodes (classes II and III). The phenotypic effects of most G6PD variants have been reported, providing an opportunity to correlate phenotypic and structural information. In ...[more]

PMID: 30148135

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Project description:Genetic patterns of inter-population variation are a result of different demographic and adaptive histories, which gradually shape the frequency distribution of the variants. However, the study of clinically relevant mutations has a Eurocentric bias. The Romani, the largest transnational minority ethnic group in Europe, originated in South Asia and received extensive gene flow from West Eurasia. Most medical genetic studies have only explored founder mutations related to Mendelian disorders in this population. Here we analyze exome sequences and genome-wide array data of 89 healthy Spanish Roma individuals to study complex traits and disease. We apply a different framework and focus on variants with both increased and decreased allele frequencies, taking into account their local ancestry. We report several OMIM traits enriched for genes with deleterious variants showing increased frequencies in Roma or in non-Roma (e.g., obesity is enriched in Roma, with an associated variant linked to South Asian ancestry; while non-insulin dependent diabetes is enriched in non-Roma Europeans). In addition, previously reported pathogenic variants also show differences among populations, where some variants segregating at low frequency in non-Roma are virtually absent in the Roma. Lastly, we describe frequency changes in drug-response variation, where many of the variants increased in Roma are clinically associated with metabolic and cardiovascular-related drugs. These results suggest that clinically relevant variation in Roma cannot only be characterized in terms of founder mutations. Instead, we observe frequency differences compared to non-Roma: some variants are absent, while other have drifted to higher frequencies. As a result of the admixture events, these clinically damaging variants can be traced back to both European and South Asian-related ancestries. This can be attributed to a different prevalence of some genetic disorders or to the fact that genetic susceptibility variants are mostly studied in populations of European descent, and can differ in individuals with different ancestries.

Dataset Information

Structural analysis of clinically relevant pathogenic G6PD variants reveals the importance of tetramerization for G6PD activity.

Publications

Structural analysis of clinically relevant pathogenic G6PD variants reveals the importance of tetramerization for G6PD activity.

Similar Datasets

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