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<jats:sec><jats:title>Objective</jats:title><jats:p>To examine the genotype to phenotype connection in glucose transporter type 1 (GLUT1) deficiency and whether a simple functional assay can predict disease outcome from genetic sequence alone.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>GLUT1 deficiency, due to mutations in <jats:italic>SLC2A1</jats:italic>, causes a wide range of epilepsies. One possible mechanism for this is variable impact of mutations on GLUT1 function. To test this, we measured glucose transport by GLUT1 variants identified in population controls and patients with mild to severe epilepsies. Controls were reference sequence from the NCBI and 4 population missense variants chosen from public reference control databases. Nine variants associated with epilepsies or movement disorders, with normal intellect in all individuals, formed the mild group. The severe group included 5 missense variants associated with classical GLUT1 encephalopathy. GLUT1 variants were expressed in <jats:italic>Xenopus laevis</jats:italic> oocytes, and glucose uptake was measured to determine kinetics (V<jats:sub>max</jats:sub>) and affinity (K<jats:sub>m</jats:sub>).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Disease severity inversely correlated with rate of glucose transport between control (V<jats:sub>max</jats:sub> = 28 ± 5), mild (V<jats:sub>max</jats:sub> = 16 ± 3), and severe (V<jats:sub>max</jats:sub> = 3 ± 1) groups, respectively. Affinities of glucose binding in control (K<jats:sub>m</jats:sub> = 55 ± 18) and mild (K<jats:sub>m</jats:sub> = 43 ± 10) groups were not significantly different, whereas affinity was indeterminate in the severe group because of low transport rates. Simplified analysis of glucose transport at high concentration (100 mM) was equally effective at separating the groups.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Disease severity can be partly explained by the extent of GLUT1 dysfunction. This simple <jats:italic>Xenopus</jats:italic> oocyte assay complements genetic and clinical assessments. In prenatal diagnosis, this simple oocyte glucose uptake assay could be useful because standard clinical assessments are not available.</jats:p></jats:sec>

Original publication

DOI

10.1212/nxg.0000000000000297

Type

Journal article

Journal

Neurology Genetics

Publisher

Ovid Technologies (Wolters Kluwer Health)

Publication Date

12/2018

Volume

4

Pages

e297 - e297