Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families.

Objective: To investigate the frequencies of the major maturity-onset diabetes of the young (MODY) subtypes in a panel of Spanish families and to assess phenotypic differences in patients with the different subtypes of MODY. Methods: Forty-eight subjects from twenty families with clinical diagnosis of MODY were studied. They underwent a standardised clinical examination and a 75-g oral glucose tolerance test (OGTT) was performed. Estimations of insulin sensitivity (%S) and insulin secretion capacity (%B) were calculated by the computer-solved homeostasis model assessment (HOMA). Mutations in the coding regions of hepatocyte nuclear factor (HNF)-4α/MODY1, glucokinase (GCK/MODY2) and HNF-1α/MODY3 genes were investigated by single strand comformation polymorphism and sequencing analysis. Results: Mutations in the GCK and HNF-1α genes were observed in 5 (25%) and 7 (35%) families respectively. Novel mutations included R385X, M238fsdelT, V226fsdelTinsAA and S418-7del11 in the GCK gene, and S121 fsdelC, VI33 M, R159Q and V259D in the HNF-1α gene. No MODY1 families were found. Subjects which were neither MODY2 nor MODY 3 (MODY-X) had a higher fasting glucose than subjects in the other groups. Insulin secretion capacity was similar in the three groups and the insulin sensitivity was decreased in MODY-X subjects. Glucose levels were significantly higher and insulin levels significantly lower, throughout the OGTT, in MODY 3 compared with MODY2 subjects. Conclusions: Mutations in the GCK/MODY2 and HNF-1α/MODY3 genes account for the majority of cases in a panel of Spanish MODY families, with MODY 3 being the most frequent subtype. The relative frequencies and the clinical characteristics of these MODY subtypes are in agreement with data previously reported in other European populations. MODY-X patients seem to present a heterogeneous clinical profile.