Jaclyn E Ruggiero1, Hope Northrup2,3, Kit Sing Au2. 1. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas. 2. Division of Medical Genetics, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas. 3. Shriners Hospitals for Children, Houston, Texas.
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. CONCLUSION: 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.
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. CONCLUSION: 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: H Katagiri; T Asano; H Ishihara; K Tsukuda; J L Lin; K Inukai; M Kikuchi; Y Yazaki; Y Oka Journal: J Biol Chem Date: 1992-11-05 Impact factor: 5.157
Authors: David M Blodgett; Julie K De Zutter; Kara B Levine; Pusha Karim; Anthony Carruthers Journal: J Gen Physiol Date: 2007-07-16 Impact factor: 4.086
Authors: Tina O Findley; Joy C Tenpenny; Michelle R O'Byrne; Alanna C Morrison; James E Hixson; Hope Northrup; Kit Sing Au Journal: Am J Med Genet A Date: 2017-09-26 Impact factor: 2.802