Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome

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 Sy ndrome (Glut-1 DS). The encoded protein (Glut-1), which has 12 transmembran e domains, is the major glucose transporter in the mammalian blood-brain ba rrier. The presence of GLUT1 mutations correlates with reduced cerebrospina l 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 D NA sequencing to identify novel GLUT1 mutations in 15 patients. These abnor malities include one large-scale deletion (hemizygosity), five missense mut ations (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+1de110), and one nonsense mutation (R330X). In additi on, six silent mutations were identified in exons 2, 4, 5, 9, and 10. The K 256V missense mutation involved the maternally derived allele in the patien t and one allele in his mother. A spontaneous R126L missense mutation also was present in the paternally derived allele of the patient. The apparent p athogenicity of these mutations is discussed in relation to the functional domains of Glut-1. Hum Mutat 16:224-231, 2000. (C) 2000 Wiley-Liss, Inc.