Advances in Human Biology: Combining Genetics and Molecular Biophysics to Pave the Way for Personalized Diagnostics and Medicine

Alexov, Emil

doi:10.1155/2014/471836

Cited by 13 publications

(16 citation statements)

References 219 publications

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“…Analyzing the effects of each mutation on the protein’s structure and function is very crucial in large scale analysis which is laborious and time-consuming by experimental methods. In recent years many studies have focused on the importance of in silico prediction methods in analyzing the effects of mutations on protein function18192021. Generally, these methods make their predictions based on sequence and structured based information using physiochemical properties and are benchmarked by the curators with the known datasets and performed well2223.…”

Section: Discussionmentioning

confidence: 99%

Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World

Alasmar

Bux

et al. 2016

Sci Rep

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A systematic search was implemented using four literature databases (PubMed, Embase, Science Direct and Web of Science) to capture all the causative mutations of Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDD) in the 22 Arab countries. Our search yielded 43 studies that captured 33 mutations (23 missense, one silent, two deletions, and seven intronic mutations), in 3,430 Arab patients with G6PDD. The 23 missense mutations were then subjected to phenotypic classification using in silico prediction tools, which were compared to the WHO pathogenicity scale as a reference. These in silico tools were tested for their predicting efficiency using rigorous statistical analyses. Of the 23 missense mutations, p.S188F, p.I48T, p.N126D, and p.V68M, were identified as the most common mutations among Arab populations, but were not unique to the Arab world, interestingly, our search strategy found four other mutations (p.N135T, p.S179N, p.R246L, and p.Q307P) that are unique to Arabs. These mutations were exposed to structural analysis and molecular dynamics simulation analysis (MDSA), which predicting these mutant forms as potentially affect the enzyme function. The combination of the MDSA, structural analysis, and in silico predictions and statistical tools we used will provide a platform for future prediction accuracy for the pathogenicity of genetic mutations.

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Section: Discussionmentioning

confidence: 99%

Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World

Alasmar

Bux

et al. 2016

Sci Rep

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“…In the case of G291R, two unrelated patients are known, both heterozygous for other mutations in PGM1 (either a nonsense or different missense mutant), and who have mild-moderate phenotypes [1,2,6]. Our structural studies therefore represent “personalized” crystal structures, a new tool in the growing field of precision medicine [38,39]. Such structures are likely to have a growing role in the understanding and treatment of inherited disease.…”

Section: Discussionmentioning

confidence: 99%

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Stiers

Kain

Graham

et al. 2016

Journal of Molecular Biology

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Human phosphoglucomutase 1 (PGM1) plays a central role in cellular glucose homeostasis, mediating the switch between glycolysis and gluconeogenesis through the conversion of glucose 1-phosphate and glucose 6-phosphate. Recent clinical studies have identified mutations in this enzyme as the cause of PGM1 deficiency, an inborn error of metabolism classified as both a glycogen storage disease and a congenital disorder of glycosylation. Reported here are the first crystal structures of two disease-related missense variants of PGM1, along with the structure of the wild-type enzyme. Two independent glycine to arginine substitutions (G121R and G291R), both affecting key active site loops of PGM1, are found to induce regions of structural disorder, as evidenced by a nearly complete loss of electron density for as many as 23 amino acids. The disordered regions are not contiguous in sequence to the site of mutation, and even cross domain boundaries. Other structural rearrangements include changes in the conformations of loops and side chains, some of which occur nearly 20 Å away from the site of mutation. The induced structural disorder is correlated with increased sensitivity to proteolysis and lower resolution diffraction, particularly for the G291R variant. Examination of the multi-domain effects of these G→R mutations establishes a correlation between interdomain interfaces of the enzyme and missense variants of PGM1 associated with disease. These crystal structures provide the first insights into the structural basis of enzyme dysfunction in PGM1 deficiency, and highlight a growing role for biophysical characterization of proteins in the field of precision medicine.

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“…As a natural consequence of the ongoing massive exome sequencing studies, the classification of human genetic variations and its relationship to disease susceptibility and drug response has recently gained remarkable attention and a considerable success has been achieved [1]. As a result, a variety of tools and databases were developed [2].…”

Section: Introductionmentioning

confidence: 99%

Structural and physico-chemical effects of disease and non-disease nsSNPs on proteins

Kucukkal

Petukh

et al. 2015

Current Opinion in Structural Biology

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141

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This review emphasizes the effects of naturally occurring mutations on structural features and physico-chemical properties of proteins. The basic protein characteristics considered are stability, dynamics, and the binding of proteins and methods for assessing effects of mutations on these macromolecular characteristics are briefly outlined. It is emphasized that the above entities mostly reflect global characteristics of considered macromolecules, while given mutations may alter the local structural features such as salt bridges and hydrogen bonds without affecting the global ones. Furthermore, it is pointed out that disease-causing mutations frequently involve a drastic change of amino acid physico-chemical properties such as charge, hydrophobicity, and geometry, and are less surface exposed than polymorphic mutations.

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Advances in Human Biology: Combining Genetics and Molecular Biophysics to Pave the Way for Personalized Diagnostics and Medicine

Cited by 13 publications

References 219 publications

Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World

Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Structural and physico-chemical effects of disease and non-disease nsSNPs on proteins

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