Glucokinase mutations in pediatric patients with impaired fasting glucose.
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.
['Aloi|C|C|', 'Salina|A|A|', 'Minuto|N|N|', 'Tallone|R|R|', 'Lugani|F|F|', 'Mascagni|A|A|', 'Mazza|O|O|', 'Cassanello|M|M|', 'Maghnie|M|M|', "d'Annunzio|G|G|"]
D000293:Adolescent D000328:Adult D002648:Child D002675:Child, Preschool D015331:Cohort Studies D003924:Diabetes Mellitus, Type 2 D005215:Fasting D005260:Female D005941:Glucokinase D005947:Glucose D006579:Heterozygote D006801:Humans D015994:Incidence D007223:Infant D007558:Italy D008297:Male D020125:Mutation, Missense D010641:Phenotype D055815:Young Adult
Glucokinase Impaired fasting glucose MODY Clinical and molecular genetics Mutation screening