title: Association of facilitated glucose transporter 2 gene variants with the myelomeningocele phenotype.
abstract: BACKGROUND
  Neural tube defects (NTDs) remain the second most common cause of congenital malformations. Myelomeningocele (MM), the most common NTD compatible with survival, results from genetic and environmental factors. Epidemiologic studies and murine models support the hypotheses that obesity, diabetes and hyperglycemia confer increased risk of NTDs. Presence of wild-type facilitated glucose transporter, Glut2, in mouse embryos has been shown to increase risk for NTDs in hyperglycemic pregnancy.
  
  
  METHODS
  The GLUT2 gene of 96 MM patients was amplified, sequenced and compared with the reference sequence (NM_000340). Variants previously unreported in the single nucleotide polymorphisms (SNP) database were considered novel. Allele frequencies of reported SNPs were compared with reference populations using Fisher's exact test.
  
  
  RESULTS
  Analysis revealed three novel variants: a substitution in the core promoter region (c.-331c>t), a substitution (c.-182g>a) in the 5'-untranslated region, and a single base pair deletion (c.1441delT) in the coding sequences. Polymorphic alleles for 10 SNPs were also identified. Seven SNPs are significantly associated with MM in the Mexican American patients tested (p < 0.05) and two of the seven remained significant after Bonferroni correction.
  
  
  CONCLUSIONS
  We identified three novel variants and seven SNPs associated with MM. The novel variants in the core promoter and in the 5'-untranslated region could affect GLUT2 mRNA transcription and stability and translation efficiency. The c.1441delT variant is predicted to alter the reading frame and prematurely terminate translation of the GLUT2 protein at the C-terminus, affecting GLUT2 protein function. Presence of GLUT2 variants may disrupt GLUT2 activity and influence MM susceptibility.
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Jaclyn E
authors.initials: JE
authors.lastname: Ruggiero
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas.|Shriners Hospitals for Children, Houston, Texas.
authors.forename: Hope
authors.initials: H
authors.lastname: Northrup
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Kit Sing
authors.initials: KS
authors.lastname: Au
mesh_terms: D001483:Base Sequence; D005787:Gene Frequency; D056726:Genetic Association Studies; D051273:Glucose Transporter Type 2 / Q000235:genetics*; D006801:Humans; D015141:Los Angeles; D008591:Meningomyelocele / Q000235:genetics*; D017058:Mexican Americans / Q000235:genetics*; D008969:Molecular Sequence Data; D009864:Ontario; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013781:Texas
chemical_list: D051273:Glucose Transporter Type 2; C495680:SLC2A2 protein, human
keywords: association; facilitated glucose transporter 2; myelomeningocele; neural tube defects; novel variants; single nucleotide polymorphism