Monogenic diabetes is triggered by mutations of a small number of genes, resulting in disrupted insulin production. Around half of the patients suffering from monogenic diabetes seem to carry a mutation in the glucokinase (GCK) gene. To date, more than 600 GCK mutations have surfaced, and around 65% of these are missense, what experts define as a genetic change resulting in the substitution of one amino acid in a protein for another. Researchers in Slovakia and the United Kingdom have identified the minimum prevalence of GCK-monogenic diabetes among Slovaks. They sequenced GCK in 100 Slovaks with a phenotype consistent with GCK-monogenic diabetes. The team also investigated, through family and functional studies, how identified variants can cause disease. Presented in the journal PLoS ONE, the study was backed by the CEED3 ('Collaborative European effort to develop diabetes diagnostics') project, which has clinched EUR 3 million under the Health Theme of the EU's Seventh Framework Programme (FP7).
Researchers from the Institute of Experimental Endocrinology, the Children Diabetes Centre and the Centre for Molecular Medicine at the Slovak Academy of Science, as well as from the Oxford Centre for Diabetes Endocrinology and Metabolism, and the Oxford Biomedical Research Centre at the University of Oxford in the United Kingdom identified 22 mutations, of which 7 were new, in 36 families.
After performing bioinformatic analysis, the researchers predicated all missense mutations, which totalled 22, that were damaging. In total, nine mutations were functionally evaluated. They found pathogenicity for seven mutants with apparently lower glucokinase activity. According to the researchers, the minimum prevalence of GCK-monogenic diabetes amongst Slovakian patients with diabetes was 0.03%.
Identifying patients with GCK-monogenic diabetes (also called maturity-onset diabetes of the young, MODY) is significant because their diagnosis has an impact on their clinical management and prognosis. It also affects members of their families.
'We have screened 100 Slovakian probands with a phenotype consistent with GCK-monogenic diabetes and identified variants in 36% (36/100) of cases,' the authors wrote in their study. 'The majority (77%), of variants are missense and a recent study has highlighted the importance of using a combination of family, bioinformatic and
functional studies to correctly assign pathogenicity.'
The researchers chose all new missense mutations as well as those that had no clear consensus on pathogenicity from bioinformatic analysis to investigate this issue further and to complement their genetic and in silico studies.
'We calculated the minimum prevalence of the GCK-monogenic diabetes in Slovakia as 20.0 cases per million which is higher than in 2 recent studies from the United Kingdom,' the authors wrote. 'This number is still very likely to be underestimated since a substantial proportion of cases will remain undiagnosed as GCK-monogenic diabetes is largely an asymptomatic disorder.'
Because symptoms are not always obvious, the researchers said it is important to perform population studies in order to accurately determine the prevalence of GCK mutations. 'Interestingly, two non-synonymous mutations, L315H and I436N,
have previously been identified only in Czech families, and a recent study showed that L315H is one of the most prevalent GCK mutations in the Czech population,' the authors wrote. 'This finding could suggest potential existence of the founder effect in Slovak and Czech families.'
The researchers said their findings offer the first evaluation of the prevalence of GCK-monogenic diabetes in Slovakia, showing that family, bioinformatic and functional studies can be used in combination to assign pathogenicity to missense GCK mutations.