The Human Gene Mutation Database (HGMD) and Its Exploitation in the Study of Mutational Mechanisms

Cooper, David Neil; Stenson, Peter D.; Chuzhanova, NA

doi:10.1002/0471250953.bi0113s12

Cited by 65 publications

(54 citation statements)

References 28 publications

(36 reference statements)

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“…Missense mutations are the most common genetic variation associated with monogenic disease, with >70,000 examples currently found in the Human Gene Mutation Database [21]. Decreased stability and folding problems are estimated to account for the pathogenicity of more than two-thirds of these [22,23], resulting in problems such as aggregation, improper trafficking, and rapid degradation.…”

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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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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“…The set of disease-associated mutations were found using the Human Genome Mutation Database (47). Human ferritin is involved in iron regulation; dysfunctions in the protein have been linked to diseaseassociated nSNV(s) manifested through anemia, cataract syndrome (48), basal ganglia disease (49,50), Parkinson's disease (51), Huntington's disease (52), Alzheimer's disease, Hallverordern-Spatz syndrome (51)(52)(53), and an array of other neurodegenerative diseases.…”

Section: Human Ferritin Proteinmentioning

confidence: 99%

The Role of Conformational Dynamics and Allostery in the Disease Development of Human Ferritin

Kumar

Glembo

Ozkan

2015

Biophysical Journal

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Determining the three-dimensional structure of myoglobin, the first solved structure of a protein, fundamentally changed the way protein function was understood. Even more revolutionary was the information that came afterward: protein dynamics play a critical role in biological functions. Therefore, understanding conformational dynamics is crucial to obtaining a more complete picture of protein evolution. We recently analyzed the evolution of different protein families including green fluorescent proteins (GFPs), β-lactamase inhibitors, and nuclear receptors, and we observed that the alteration of conformational dynamics through allosteric regulation leads to functional changes. Moreover, proteome-wide conformational dynamics analysis of more than 100 human proteins showed that mutations occurring at rigid residue positions are more susceptible to disease than flexible residue positions. These studies suggest that disease-associated mutations may impair dynamic allosteric regulations, leading to loss of function. Thus, in this study, we analyzed the conformational dynamics of the wild-type light chain subunit of human ferritin protein along with the neutral and disease forms. We first performed replica exchange molecular dynamics simulations of wild-type and mutants to obtain equilibrated dynamics and then used perturbation response scanning (PRS), where we introduced a random Brownian kick to a position and computed the fluctuation response of the chain using linear response theory. Using this approach, we computed the dynamic flexibility index (DFI) for each position in the chain for the wild-type and the mutants. DFI quantifies the resilience of a position to a perturbation and provides a flexibility/rigidity measurement for a given position in the chain. The DFI analysis reveals that neutral variants and the wild-type exhibit similar flexibility profiles in which experimentally determined functionally critical sites act as hinges in controlling the overall motion. However, disease mutations alter the conformational dynamic profile, making hinges more loose (i.e., softening the hinges), thus impairing the allosterically regulated dynamics.

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“…One chain on each dimer is color-coded by its f-DFI score (0 to 1) for each residue, where blue indicates low f-DFI and red high f-DFI [63]. On the left AGT displays 3 neutral mutations, while on the right Hex A shows 4 known disease-associated mutations purported by the Human Gene Mutation Database (HGMD) [87]. None of the mutations are located at hotspots, making them difficult to predict.…”

Section: Figurementioning

confidence: 99%

Integration of structural dynamics and molecular evolution via protein interaction networks: a new era in genomic medicine

Kumar

Butler

Kumar

et al. 2015

Current Opinion in Structural Biology

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Summary Sequencing technologies are revealing many new non-synonymous single nucleotide variants (nsSNVs) in each personal exome. To assess their functional impacts, comparative genomics is frequently employed to predict if they are benign or not. However, evolutionary analysis alone is insufficient, because it misdiagnoses many disease-associated nsSNVs, such as those at positions involved in protein interfaces, and because evolutionary predictions do not provide mechanistic insights into functional change or loss. Structural analyses can aid in overcoming both of these problems by incorporating conformational dynamics and allostery in nSNV diagnosis. Finally, protein-protein interaction networks using systems-level methodologies shed light onto disease etiology and pathogenesis. Bridging these network approaches with structurally resolved protein interactions and dynamics will advance genomic medicine.

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The Human Gene Mutation Database (HGMD) and Its Exploitation in the Study of Mutational Mechanisms

Cited by 65 publications

References 28 publications

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

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

The Role of Conformational Dynamics and Allostery in the Disease Development of Human Ferritin

Integration of structural dynamics and molecular evolution via protein interaction networks: a new era in genomic medicine

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