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

Objective: To investigate the frequencies of the major maturity-onset diabe tes of the young (MODY) subtypes in a panel of Spanish families and to asse ss 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 an d a 75-g oral glucose tolerance test (OGTT) was performed. Estimations of i nsulin sensitivity (%S) and insulin secretion capacity (%B) were calculated by the computer-solved homeostasis model assessment (HOMA). Mutations in t he coding regions of hepatocyte nuclear factor (HNF)4 alpha/MODY1, glucokin ase (GCK/MODY2) and HNF-1 alpha/MODY3 genes were investigated by single str and comformation polymorphism and sequencing analysis, Results: Mutations in the GCK and HNF-1 alpha genes were observed in 5 (25% ) and 7 (35%) families respectively. Novel mutations included R385X, M238fs delT, V226fsdelTinsAA and S418-7del11 in the GCK gene, and S121 fsdelC, V13 3M, R159Q and V259D in the HNF-1 alpha gene. No MODY1 families were found. Subjects which were neither MODY? nor MODY3 (MODY-X) had a higher fasting g lucose than subjects in the other groups. Insulin secretion capacity was si milar in the three groups and the insulin sensitivity was decreased in MODY -X subjects. Glucose levels were significantly higher and insulin levels si gnificantly lower, throughout the OGTT, in MODY3 compared with MODY2 subjec ts. Conclusions: Mutations in the GCK/MODY2 and HNF-1 alpha/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 previous ly reported in other European populations. MODY-X patients seem to present a heterogeneous clinical profile.