title: Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome.
abstract: Fifteen children presenting with infantile seizures, acquired microcephaly, and developmental delay were found to have novel heterozygous mutations in the GLUT1 (SLC2A1). We refer to this condition as the Glut-1 Deficiency Syndrome (Glut-1 DS). The encoded protein (Glut-1), which has 12 transmembrane domains, is the major glucose transporter in the mammalian blood-brain barrier. The presence of GLUT1 mutations correlates with reduced cerebrospinal fluid glucose concentrations (hypoglycorrhachia) and reduced erythrocyte glucose transporter activities in the patients. We used Florescence in situ hybridization, PCR, single-stranded DNA conformational polymorphism, and DNA sequencing to identify novel GLUT1 mutations in 15 patients. These abnormalities include one large-scale deletion (hemizygosity), five missense mutations (S66F, R126L, E146K, K256V, R333W), three deletions (266delC, 267A>T; 904delA; 1086delG), three insertions (368-369 insTCCTGCCCACCACGCTCACCACG, 741-742insC, 888-889insG), three splice site mutations (197+1G>A; 1151+1G>T; 857T>G, 858G>A, 858+1del10), and one nonsense mutation (R330X). In addition, six silent mutations were identified in exons 2, 4, 5, 9, and 10. The K256V missense mutation involved the maternally derived allele in the patient and one allele in his mother. A spontaneous R126L missense mutation also was present in the paternally derived allele of the patient. The apparent pathogenicity of these mutations is discussed in relation to the functional domains of Glut-1.
authors.affiliation: Colleen Giblin Laboratories for Pediatric Neurology Research, Department of Neurology, Columbia University, New York, New York, USA.
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Kranz-Eble
authors.forename: D C
authors.initials: DC
authors.lastname: De Vivo
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence / Q000235:genetics; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics*; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis; D006580:Genetic Carrier Screening; D051272:Glucose Transporter Type 1; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics; D013577:Syndrome
chemical_list: D018389:Codon, Nonsense; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D022821:RNA Splice Sites; C495677:SLC2A1 protein, human