title: Autosomal dominant transmission of GLUT1 deficiency.
abstract: GLUT1 deficiency is caused by a defect in the facilitative glucose transporter GLUT1. Impaired glucose transport across brain tissue barriers is reflected by hypoglycorrhachia and results in an epileptic encephalopathy with developmental delay and motor disorders. Recently heterozygous mutations in the GLUT1 gene (1p35-31.3) have been reported in sporadic patients. Parents and siblings carried the GLUT1 wild-type, suggesting a de novo, autosomal dominant condition resulting from GLUT1 haploinsufficiency. We report a father and two children from separate marriages affected by GLUT1 deficiency and carrying a novel heterozygous missense mutation (G272A) in the GLUT1 gene. Mutations were identified by polymerase chain reaction and DNA sequencing and confirmed by restriction fragment digest. The predicted amino acid change (Gly91Asp) affects an Arg-X-Gly-Arg-Arg motif between helices 2 and 3 that represents a cytoplasmic anchor point and is highly conserved among transporters of the major facilitator superfamily down to yeast and bacteria. GLUT1 immunoreactivity was normal, but 3-O-methyl-D-glucose uptake into erythrocytes was significantly reduced, suggesting a quantitatively normal, but functionally impaired, GLUT1 protein at the cell membrane. This is the first report of autosomal dominant transmission of GLUT1 deficiency, confirming that this condition is the result of haploinsufficiency. The Gly-->Asp mutation within a highly conserved sequence highlights its importance for GLUT1 function. GLUT1 deficiency should be considered in patients with epilepsy, mental retardation and motor disorders. Our observations have bearing on the identification of this treatable disorder in pediatric and adult patients, will modify current biochemical protocols which use parental controls and will enable genetic counseling of affected families.
authors.affiliation: University of Essen, Department of Pediatric Neurology, Hufelandstrasse 55, D-45122 Essen, Germany. joerg.klepper@uni-essen.de
authors.forename: J
authors.initials: J
authors.lastname: Klepper
authors.forename: M
authors.initials: M
authors.lastname: Willemsen
authors.forename: A
authors.initials: A
authors.lastname: Verrips
authors.forename: E
authors.initials: E
authors.lastname: Guertsen
authors.forename: R
authors.initials: R
authors.lastname: Herrmann
authors.forename: C
authors.initials: C
authors.lastname: Kutzick
authors.forename: A
authors.initials: A
authors.lastname: Flörcken
authors.forename: T
authors.initials: T
authors.lastname: Voit
mesh_terms: D019325:3-O-Methylglucose / Q000493:pharmacokinetics; D000328:Adult; D020816:Amino Acid Motifs; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D004591:Electrophoresis, Polyacrylamide Gel; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D051272:Glucose Transporter Type 1; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D013129:Spinal Puncture
chemical_list: D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; D019325:3-O-Methylglucose