AUTHOR=Zimmermann Michael T. , Urrutia Raul , Cousin Margot A. , Oliver Gavin R. , Klee Eric W. 

TITLE=Assessing Human Genetic Variations in Glucose Transporter SLC2A10 and Their Role in Altering Structural and Functional Properties

JOURNAL=Frontiers in Genetics

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00276

DOI=10.3389/fgene.2018.00276

ISSN=1664-8021

ABSTRACT=<p><bold>Purpose:</bold> Demand is increasing for clinical genomic sequencing to provide diagnoses for patients presenting phenotypes indicative of genetic diseases, but for whom routine genetic testing failed to yield a diagnosis. DNA-based testing using high-throughput technologies often identifies variants with insufficient evidence to determine whether they are disease-causal or benign, leading to categorization as variants of uncertain significance (VUS).</p><p><bold>Methods:</bold> We used molecular modeling and simulation to generate specific hypotheses for the molecular effects of variants in the human glucose transporter, GLUT10 (<italic>SLC2A10</italic>). Similar to many disease-relevant membrane proteins, no experimentally derived 3D structure exists. An atomic model was generated and used to evaluate multiple variants, including pathogenic, benign, and VUS.</p><p><bold>Results:</bold> These analyses yielded detailed mechanistic data, not currently predictable from sequence, including altered protein stability, charge distribution of ligand binding surfaces, and shifts toward or away from transport-competent conformations. Consideration of the two major conformations of GLUT10 was important as variants have conformation-specific effects. We generated detailed molecular hypotheses for the functional impact of variants in GLUT10 and propose means to determine their pathogenicity.</p><p><bold>Conclusion:</bold> The type of workflow we present here is valuable for increasing the throughput and resolution with which VUS effects can be assessed and interpreted.</p>