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Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome
D Wang1, P Kranz-Eble, D C De Vivo
1Colleen Giblin Laboratories for Pediatric Neurology Research, Department of Neurology, Columbia University, New York, New York, USA.
Insights
Novel mutations in the GLUT1 gene cause Glut-1 Deficiency Syndrome (Glut-1 DS), leading to infantile seizures, microcephaly, and developmental delay in children. This genetic condition impairs glucose transport across the blood-brain barrier.
Area of Science:
- Genetics
- Neuroscience
- Biochemistry
Background:
- Infantile seizures, microcephaly, and developmental delay can indicate underlying metabolic disorders.
- The GLUT1 (SLC2A1) gene encodes the primary glucose transporter at the blood-brain barrier, crucial for brain energy metabolism.
- Defects in glucose transport can lead to neurological dysfunction.
Purpose of the Study:
- To identify genetic mutations associated with a specific neurodevelopmental disorder.
- To characterize the spectrum of GLUT1 mutations in affected children.
- To correlate genotype with observed clinical phenotypes and biochemical findings.
Main Methods:
- Genetic analysis including Florescence in situ hybridization, PCR, single-stranded DNA conformational polymorphism, and DNA sequencing.
- Identification and classification of various mutation types within the GLUT1 gene.
- Biochemical assays measuring cerebrospinal fluid glucose and erythrocyte glucose transporter activity.
Main Results:
- Novel heterozygous mutations in the GLUT1 gene were identified in 15 children with infantile seizures, microcephaly, and developmental delay.
- A diverse range of GLUT1 mutations were found, including deletions, insertions, missense, nonsense, and splice site mutations.
- Patients exhibited reduced cerebrospinal fluid glucose (hypoglycorrhachia) and decreased erythrocyte glucose transporter activity, consistent with Glut-1 Deficiency Syndrome (Glut-1 DS).
Conclusions:
- Genetic mutations in GLUT1 are the cause of Glut-1 Deficiency Syndrome (Glut-1 DS).
- The identified GLUT1 mutations disrupt glucose transport, leading to severe neurological and developmental impairments.
- Understanding these mutations aids in diagnosing and potentially managing this rare genetic disorder.
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.