Cunningham Anna D, Colavin Alexandre, Huang Kerwyn Casey, Mochly-Rosen Daria
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Biophysics Program, Stanford University, Stanford, CA 94305, USA.
Cell Rep. 2017 Mar 14;18(11):2592-2599. doi: 10.1016/j.celrep.2017.02.048.
G6PD deficiency, an enzymopathy affecting 7% of the world population, is caused by over 160 identified amino acid variants in glucose-6-phosphate dehydrogenase (G6PD). The clinical presentation of G6PD deficiency is diverse, likely due to the broad distribution of variants across the protein and the potential for multidimensional biochemical effects. In this study, we use bioinformatic and biochemical analyses to interpret the relationship between G6PD variants and their clinical phenotype. Using structural information and statistical analyses of known G6PD variants, we predict the molecular phenotype of five uncharacterized variants from a reference population database. Through multidimensional analysis of biochemical data, we demonstrate that the clinical phenotypes of G6PD variants are largely determined by a trade-off between protein stability and catalytic activity. This work expands the current understanding of the biochemical underpinnings of G6PD variant pathogenicity and suggests a promising avenue for correcting G6PD deficiency by targeting essential structural features of G6PD.
葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症是一种影响全球7%人口的酶病，由葡萄糖-6-磷酸脱氢酶中160多种已确定的氨基酸变体引起。G6PD缺乏症的临床表现多种多样，这可能是由于变体在蛋白质中的广泛分布以及多维生化效应的可能性。在本研究中，我们使用生物信息学和生化分析来解释G6PD变体与其临床表型之间的关系。利用已知G6PD变体的结构信息和统计分析，我们从参考人群数据库中预测了五个未表征变体的分子表型。通过对生化数据的多维分析，我们证明G6PD变体的临床表型在很大程度上由蛋白质稳定性和催化活性之间的权衡决定。这项工作扩展了目前对G6PD变体致病性生化基础的理解，并为通过靶向G6PD的基本结构特征来纠正G6PD缺乏症提出了一条有前景的途径。
