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.
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Acknowledgements
We would like to thank Prof. Gianmarco Ghiggeri, MD. We also thank Anna Capurro for English language revision of the manuscript.
Authors’ contributions
AS and CA conceived and designed the experiments, performed molecular investigation, analyzed data, performed computational analysis, drafted and revised the manuscript, and approved the final manuscript as submitted. NM, RT made clinical diagnosis. FL analyzed data. AM performed β-cell autoantibody detection test. OM, MC revised the manuscript. MM critically reviewed the manuscript and approved the final manuscript as submitted. GdA made clinical diagnosis, conceptualized and designed the study, critically reviewed the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.
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Aloi, C., Salina, A., Minuto, N. et al. Glucokinase mutations in pediatric patients with impaired fasting glucose. Acta Diabetol 54, 913–923 (2017). https://doi.org/10.1007/s00592-017-1021-y
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DOI: https://doi.org/10.1007/s00592-017-1021-y