title: Genetic and bioinformatics analysis of four novel GCK missense variants detected in Caucasian families with GCK-MODY phenotype.
abstract: Heterozygous loss-of-function mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (MODY) subtype GCK (GCK-MODY/MODY2). GCK sequencing revealed 16 distinct mutations (13 missense, 1 nonsense, 1 splice site, and 1 frameshift-deletion) co-segregating with hyperglycaemia in 23 GCK-MODY families. Four missense substitutions (c.718A>G/p.Asn240Asp, c.757G>T/p.Val253Phe, c.872A>C/p.Lys291Thr, and c.1151C>T/p.Ala384Val) were novel and a founder effect for the nonsense mutation (c.76C>T/p.Gln26*) was supposed. We tested whether an accurate bioinformatics approach could strengthen family-genetic evidence for missense variant pathogenicity in routine diagnostics, where wet-lab functional assays are generally unviable. In silico analyses of the novel missense variants, including orthologous sequence conservation, amino acid substitution (AAS)-pathogenicity predictors, structural modeling and splicing predictors, suggested that the AASs and/or the underlying nucleotide changes are likely to be pathogenic. This study shows how a careful bioinformatics analysis could provide effective suggestions to help molecular-genetic diagnosis in absence of wet-lab validations.
authors.affiliation: Regional Center for Pediatric Diabetes, Clinical Nutrition and Obesity, Department of Life and Reproduction Sciences.
authors.forename: S
authors.initials: S
authors.lastname: Costantini
authors.forename: G
authors.initials: G
authors.lastname: Malerba
authors.forename: G
authors.initials: G
authors.lastname: Contreas
authors.forename: M
authors.initials: M
authors.lastname: Corradi
authors.forename: S P
authors.initials: SP
authors.lastname: Marin Vargas
authors.forename: A
authors.initials: A
authors.lastname: Giorgetti
authors.forename: C
authors.initials: C
authors.lastname: Maffeis
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D044465:White People / Q000235:genetics*
chemical_list: D005941:Glucokinase
keywords: GCK; MODY; bioinformatics analysis; co-segregation analysis; missense variant; pathogenicity prediction; splicing prediction