Genetic and bioinformatics analysis of four novel GCK missense variants detected in Caucasian families with GCK‐MODY phenotype. (6th June 2014)

• Record Type: Journal Article
• Authors: Costantini, S.; Malerba, G.; Contreas, G.; Corradi, M.; Marin Vargas, S.P.; Giorgetti, A.; Maffeis, C.
• Is Part Of: Clinical genetics. Volume 87:Number 5(2015:May)
• Page Start: 440
• Page End: 447
• Publication Date: 2014-06-06
• Subjects: Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12406
• Languages: English
• ISSNs: 0009-9163

Abstract

<abstract abstract-type="main" id="cge12406-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="cge12406-para-0001">Heterozygous loss‐of‐function mutations in the glucokinase (<italic>GCK</italic>) gene cause maturity‐onset diabetes of the young (MODY) subtype GCK (GCK‐MODY/MODY2). <italic>GCK</italic> 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&gt;G/p.Asn240Asp, c.757G&gt;T/p.Val253Phe, c.872A&gt;C/p.Lys291Thr, and c.1151C&gt;T/p.Ala384Val) were novel and a founder effect for the nonsense mutation (c.76C&gt;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. <italic>In silico</italic> 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.</p> </abstract>