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

• Main Authors: Michael T. Zimmermann, Raul Urrutia, Margot A. Cousin, Gavin R. Oliver, Eric W. Klee
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-07-01
• Series: Frontiers in Genetics
• Subjects: genetics; molecular modeling; natural variation; variant of uncertain significance; ATS
• Online Access: https://www.frontiersin.org/article/10.3389/fgene.2018.00276/full

Purpose: 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).Methods: We used molecular modeling and simulation to generate specific hypotheses for the molecular effects of variants in the human glucose transporter, GLUT10 (SLC2A10). 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.Results: 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.Conclusion: The type of workflow we present here is valuable for increasing the throughput and resolution with which VUS effects can be assessed and interpreted.