Disease-associated Glut1 single amino acid substitute mutations S66F, R126C, and T295M constitute Glut1-deficiency states in vitro
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AbstractGlucose transporter type 1 deficiency syndrome (Glut1DS) is the result of autosomal-dominant loss-offunction mutation of the glucose transporter type 1 gene (GLUT1) leading to brain energy failure and epileptic encephalopathy. In this study, the protein products of the Glut1DS-associated GLUT1 missense mutations, S66F, R126C, and T295M, were characterized using the Glut1-green fluorescent protein (GFP) fusion expressed in CHO cells. Glut1-GFP expression was confirmed by Western blot and confocal microscopy. The applicability of this Glut1-GFP expression model in reporting Glut I functional deticits was validated by re-confirming the glucose transport defects of the previously reported pathogenic mutations R126H, R126L, and R333W. While S66F, R126C, and T295M mutants were expressed and targeted to the cell membrane, these Glut1 mutants have significantly diminished membrane association and glucose transport activity (p < 0.05) relative to the wild-type Glut1 protein. Consistent with the reduced Glut1 membrane association, glucose transport kinetics studies showed that S66F, R126C, and T295M mutants have significantly reduced (p < 0.05) V-max but not K-m. Thus, Glut1 single amino acid substitute mutants S66F, R126C, and T295M impair glucose transport function and constitute Glut1-deficiency states in vitro. These results support the pathogenicity of Glut1 S66F, R126C, and T295M in vivo. (c) 2006 Elsevier Inc. All rights reserved.
All Author(s) ListWong HY, Law PY, Ho YY
Journal nameMolecular Genetics and Metabolism
Volume Number90
Issue Number2
Pages193 - 198
LanguagesEnglish-United Kingdom
Keywordsblood-brain barrier; epilepsy; Glut1; Glut1-deficiency syndrome; green fluorescent protein
Web of Science Subject CategoriesBIOCHEMISTRY & MOLECULAR BIOLOGY; Endocrinology & Metabolism; Genetics & Heredity; GENETICS & HEREDITY; Medicine, Research & Experimental; MEDICINE, RESEARCH & EXPERIMENTAL; Research & Experimental Medicine

Last updated on 2021-15-06 at 00:34