Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy

Type 2 Maturity Onset Diabetes of the Young (MODY2) is a monogenic autosomal disease characterized by a primary defect in insulin secretion and hyperglycemia. It results from GCK gene mutations that impair enzyme activity. Between 2006 and 2010, we investigated GCK mutations in 66 diabetic children...

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Main Authors:	Capuano, Marina, Garcia-Herrero, Carmen Maria, Tinto, Nadia, Carluccio, Carla, Capobianco, Valentina, Coto, Iolanda, Cola, Arturo, Iafusco, Dario, Franzese, Adriana, Zagari, Adriana, Navas, Maria Angeles, Sacchetti, Lucia
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385652/

id	pubmed-3385652
recordtype	oai_dc
spelling	pubmed-33856522012-07-03 Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy Capuano, Marina Garcia-Herrero, Carmen Maria Tinto, Nadia Carluccio, Carla Capobianco, Valentina Coto, Iolanda Cola, Arturo Iafusco, Dario Franzese, Adriana Zagari, Adriana Navas, Maria Angeles Sacchetti, Lucia Research Article Type 2 Maturity Onset Diabetes of the Young (MODY2) is a monogenic autosomal disease characterized by a primary defect in insulin secretion and hyperglycemia. It results from GCK gene mutations that impair enzyme activity. Between 2006 and 2010, we investigated GCK mutations in 66 diabetic children from southern Italy with suspected MODY2. Denaturing High Performance Liquid Chromatography (DHPLC) and sequence analysis revealed 19 GCK mutations in 28 children, six of which were novel: p.Glu40Asp, p.Val154Leu, p.Arg447Glyfs, p.Lys458_Cys461del, p.Glu395_Arg397del and c.580-2A>T. We evaluated the effect of these 19 mutations using bioinformatic tools such as Polymorphism Phenotyping (Polyphen), Sorting Intolerant From Tolerant (SIFT) and in silico modelling. We also conducted a functional study to evaluate the pathogenic significance of seven mutations that are among the most severe mutations found in our population, and have never been characterized: p.Glu70Asp, p.His137Asp, p.Phe150Tyr, p.Val154Leu, p.Gly162Asp, p.Arg303Trp and p.Arg392Ser. These seven mutations, by altering one or more kinetic parameters, reduced enzyme catalytic activity by >40%. All mutations except p.Glu70Asp displayed thermal-instability, indeed >50% of enzyme activity was lost at 50°C/30 min. Thus, these seven mutations play a pathogenic role in MODY2 insurgence. In conclusion, this report revealed six novel GCK mutations and sheds some light on the structure-function relationship of human GCK mutations and MODY2. Public Library of Science 2012-06-20 /pmc/articles/PMC3385652/ /pubmed/22761713 http://dx.doi.org/10.1371/journal.pone.0038906 Text en Capuano et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Capuano, Marina Garcia-Herrero, Carmen Maria Tinto, Nadia Carluccio, Carla Capobianco, Valentina Coto, Iolanda Cola, Arturo Iafusco, Dario Franzese, Adriana Zagari, Adriana Navas, Maria Angeles Sacchetti, Lucia
spellingShingle	Capuano, Marina Garcia-Herrero, Carmen Maria Tinto, Nadia Carluccio, Carla Capobianco, Valentina Coto, Iolanda Cola, Arturo Iafusco, Dario Franzese, Adriana Zagari, Adriana Navas, Maria Angeles Sacchetti, Lucia Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy
author_facet	Capuano, Marina Garcia-Herrero, Carmen Maria Tinto, Nadia Carluccio, Carla Capobianco, Valentina Coto, Iolanda Cola, Arturo Iafusco, Dario Franzese, Adriana Zagari, Adriana Navas, Maria Angeles Sacchetti, Lucia
author_sort	Capuano, Marina
title	Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy
title_short	Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy
title_full	Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy
title_fullStr	Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy
title_full_unstemmed	Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy
title_sort	glucokinase (gck) mutations and their characterization in mody2 children of southern italy
description	Type 2 Maturity Onset Diabetes of the Young (MODY2) is a monogenic autosomal disease characterized by a primary defect in insulin secretion and hyperglycemia. It results from GCK gene mutations that impair enzyme activity. Between 2006 and 2010, we investigated GCK mutations in 66 diabetic children from southern Italy with suspected MODY2. Denaturing High Performance Liquid Chromatography (DHPLC) and sequence analysis revealed 19 GCK mutations in 28 children, six of which were novel: p.Glu40Asp, p.Val154Leu, p.Arg447Glyfs, p.Lys458_Cys461del, p.Glu395_Arg397del and c.580-2A>T. We evaluated the effect of these 19 mutations using bioinformatic tools such as Polymorphism Phenotyping (Polyphen), Sorting Intolerant From Tolerant (SIFT) and in silico modelling. We also conducted a functional study to evaluate the pathogenic significance of seven mutations that are among the most severe mutations found in our population, and have never been characterized: p.Glu70Asp, p.His137Asp, p.Phe150Tyr, p.Val154Leu, p.Gly162Asp, p.Arg303Trp and p.Arg392Ser. These seven mutations, by altering one or more kinetic parameters, reduced enzyme catalytic activity by >40%. All mutations except p.Glu70Asp displayed thermal-instability, indeed >50% of enzyme activity was lost at 50°C/30 min. Thus, these seven mutations play a pathogenic role in MODY2 insurgence. In conclusion, this report revealed six novel GCK mutations and sheds some light on the structure-function relationship of human GCK mutations and MODY2.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385652/
_version_	1611539936606945280

Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy

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