title: Identification of novel polymorphisms in the glucokinase and glucose-6-phosphatase genes in infants who died suddenly and unexpectedly.
abstract: Sudden and unexpected infant deaths can be unexplained [sudden infant death syndrome (SIDS)] or explained (non-SIDS) but risk factors including lower birthweight are similar in both groups. Mutations in the glucokinase (GK) gene result in Maturity Onset Diabetes of the Young type 2 (MODY 2) and are associated with lower birthweight. Low hepatic glucose-6-phosphatase (G6PC1) expression occurs in both low birthweight and SIDS infants. We investigated whether polymorphisms are prevalent in the GK and G6PC1 genes in infants who died suddenly and unexpectedly. Mutation analysis was performed by polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) in samples from 126 infants who died suddenly and unexpectedly (78 SIDS, 48 non-SIDS) and from 70 healthy, living infants. G6PC1 promoter polymorphism significance was investigated by transfection of reporter gene constructs into a H4IIE cell line. Heterozygous GK polymorphisms were identified in 17.9% of SIDS and 20.8% of non-SIDS infants: two rare silent polymorphisms, Y215Y and S263S, in the coding region; a third rare polymorphism, -45G>A, in the hepatic promoter and the most prevalent polymorphism, c.484-29G>C, in a non-coding region upstream from the intron 4-exon 5 junction. A novel heterozygous polymorphism -77G>A in the G6PC1 promoter in 6.3% of non-SIDS and 2.9% of control infants decreased basal G6PC1 promoter activity (p<0.001). We describe three novel polymorphisms in the GK gene, S263S, -45G>A, and a common (14.3%) intronic substitution, c.484-29G>C, in infants who died suddenly and unexpectedly. We identified the first G6PC1 promoter polymorphism, which lowers expression, potentially increasing risk of hypoglycaemia and hence risk of sudden and unexpected death.
authors.affiliation: Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Forsyth
authors.forename: Robert
authors.initials: R
authors.lastname: Hume
authors.forename: Allan
authors.initials: A
authors.lastname: Howatson
authors.forename: Anthony
authors.initials: A
authors.lastname: Busuttil
authors.forename: Ann
authors.initials: A
authors.lastname: Burchell
mesh_terms: D000818:Animals; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D051381:Rats; D013398:Sudden Infant Death / Q000235:genetics*
chemical_list: D005941:Glucokinase; D005952:Glucose-6-Phosphatase