C Aloi1, A Salina1, N Minuto2, R Tallone2, F Lugani3, A Mascagni4, O Mazza5, M Cassanello5, M Maghnie6, G d'Annunzio7. 1. Laboratory of Diabetology - Laboratory for the Study of Inborn Errors of Metabolism, Istituto Giannina Gaslini, Genoa, Italy. 2. Pediatric Clinic, Regional Center of Diabetes, Istituto Giannina Gaslini, Via G. Gaslini, 5, 16147, Genoa, Italy. 3. Laboratory of Pathophysiology of Uremia, Istituto Giannina Gaslini, Genoa, Italy. 4. Laboratory for the Study of Inborn Errors of Metabolism, DINOGMI, University of Genoa, Genoa, Italy. 5. Laboratory for the Study of Inborn Errors of Metabolism, Istituto Giannina Gaslini, Genoa, Italy. 6. Pediatric Clinic, University of Genoa, Genoa, Italy. 7. Pediatric Clinic, Regional Center of Diabetes, Istituto Giannina Gaslini, Via G. Gaslini, 5, 16147, Genoa, Italy. giuseppedannunzio@gaslini.org.
Abstract
AIMS: Our aim was to detect the frequency of glucokinase (GCK) gene mutations in a cohort of patients with impaired fasting glucose and to describe the clinical manifestations of identified variants. We also aimed at predicting the effect of the novel missense mutations by computational approach. METHODS: Overall 100 unrelated Italian families with impaired fasting glucose were enrolled and subdivided into two cohorts according to strict and to mild criteria for diagnosis of maturity-onset diabetes of the young (MODY). GCK gene sequencing was performed in all participants. RESULTS: Fifty-three Italian families with 44 different mutations affecting the GCK and co-segregating with the clinical phenotype of GCK/MODY were identified. All mutations were in heterozygous state. In Sample 1, GCK defects were found in 32/36 (88.9%) subjects selected with strict MODY diagnostic criteria, while in Sample 2 GCK defects were found in 21/64 (32.8%) subjects selected with mild MODY diagnostic criteria. CONCLUSIONS: Our study enlarged the wide spectrum of GCK defects by adding 9 novel variants. The application of strict recruitment criteria resulted in 88.9% incidence of GCK/MODY, which confirmed it as the commonest form of MODY in the Italian population. In order to avoid misdiagnosis of GCK/MODY, it could be useful to perform molecular screening even if one or more clinical parameters for the diagnosis of MODY are missing. Computational analysis is useful to understand the effect of GCK defect on protein functionality, especially when the novel identified variant is a missense mutation and/or parents' DNA is not available.
AIMS: Our aim was to detect the frequency of glucokinase (GCK) gene mutations in a cohort of patients with impaired fasting glucose and to describe the clinical manifestations of identified variants. We also aimed at predicting the effect of the novel missense mutations by computational approach. METHODS: Overall 100 unrelated Italian families with impaired fasting glucose were enrolled and subdivided into two cohorts according to strict and to mild criteria for diagnosis of maturity-onset diabetes of the young (MODY). GCK gene sequencing was performed in all participants. RESULTS: Fifty-three Italian families with 44 different mutations affecting the GCK and co-segregating with the clinical phenotype of GCK/MODY were identified. All mutations were in heterozygous state. In Sample 1, GCK defects were found in 32/36 (88.9%) subjects selected with strict MODY diagnostic criteria, while in Sample 2 GCK defects were found in 21/64 (32.8%) subjects selected with mild MODY diagnostic criteria. CONCLUSIONS: Our study enlarged the wide spectrum of GCK defects by adding 9 novel variants. The application of strict recruitment criteria resulted in 88.9% incidence of GCK/MODY, which confirmed it as the commonest form of MODY in the Italian population. In order to avoid misdiagnosis of GCK/MODY, it could be useful to perform molecular screening even if one or more clinical parameters for the diagnosis of MODY are missing. Computational analysis is useful to understand the effect of GCK defect on protein functionality, especially when the novel identified variant is a missense mutation and/or parents' DNA is not available.
Authors: Sílvia Santos Monteiro; Tiago da Silva Santos; Liliana Fonseca; Guilherme Assunção; Ana M Lopes; Diana B Duarte; Ana Rita Soares; Francisco Laranjeira; Isaura Ribeiro; Eugénia Pinto; Sónia Rocha; Sofia Barbosa Gouveia; María Eugenia Vazquez-Mosquera; Maria João Oliveira; Teresa Borges; Maria Helena Cardoso Journal: Acta Diabetol Date: 2022-10-08 Impact factor: 4.087
Authors: Dinara E Ivanoshchuk; Elena V Shakhtshneider; Oksana D Rymar; Alla K Ovsyannikova; Svetlana V Mikhailova; Veniamin S Fishman; Emil S Valeev; Pavel S Orlov; Mikhail I Voevoda Journal: J Pers Med Date: 2021-01-18