Early-onset Type II diabetes mellitus in Italian families due to mutationsin the genes encoding hepatic nuclear factor 1 alpha and glucokinase

Aims/hypothesis. Maturity-onset-diabetes of the young (MODY) is caused by m utations in at least five different genes. Our aim was to determine the pre valence of the most common MODY genes in Italian families with early-onset Type II (non-insulin-dependent) diabetes mellitus. Methods. We screened 28 Italian early-onset Type II diabetic families (diag nosis < 35 years) for mutations in the hepatic nuclear factor-4 alpha, (MOD Y1), glucokinase (MODY2) and hepatic nuclear factor-la (MODY3). Both strand s of exons, flanking introns and minimal promoter regions of the above-ment ioned genes were amplified using polymerase chain reaction and were sequenc ed directly. Results. We identified four different mutations, three of which are not des cribed, (W113X, G42P43fsCC --> A, H514R) and four new polymorphisms (G184G, T513T, IVS3-nt47delG, IVS1- nt53C --> G) in the hepatic nuclear factor-1 a lpha gene, two new potential mutations (G44S, IVS4nt + 7C --> T) and three new polymorphisms (promoter-nt84C --> G, IVS9 + nt8C --> T, IVS9 + nt49G -- > A) in the glucokinase gene, and a new polymorphism (IVS1c-nt11T --> G) in the hepatic nuclear factor-4 alpha gene. Conclusion/interpretation. Mutations in the hepatic nuclear factor-1 alpha and glucokinase are associated with Type II diabetes in 14% and 7% of Itali an families, respectively. Our findings provide an impetus for screening It alian MODY and early-non Type II diabetic families for mutations in the abo ve mentioned genes to identify relatives at risk who could benefit from pri mary prevention care.