High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes

Aims/hypothesis. To investigate the contribution of mutations in maturity-o nset diabetes of the young (MODY) and mitochondrial genes to early-onset di abetes with a strong family history of diabetes in a cohort with a high pre valence of Type I (insulin-dependent) diabetes mellitus. Methods. Screening for sequence variants in the hepatocyte nuclear factor ( HNF)-4 alpha (MODY1), glucokinase (MODY2), HNF-1 alpha (MODY3) genes and mi tochondrial DNA was carried out in 115 Finnish and Swedish patients with ea rly-onset (less than or equal to 40 years) diabetes using the single strand conformation polymorphism (SSCP) technique and direct sequencing. Allele f requencies were compared with 118 patients with onset of diabetes Type II ( non-insulin-dependent) diabetes mellitus after the age of 40 and 92 non-dia betic control subjects without a family history of diabetes. Results. In total 52 sequence variants were found in the HNF-1 alpha, HNF-4 alpha and glucokinase genes, 12 of which were considered as MODY mutations . Three families had the A3243G mutation in the mitochondrial tRNA(Leu) gen e, which resulted in an overall pre valence of these mutations of 13%. Conclusion/interpretation. Among 115 Scandinavian families, mutations in th e HNF-1 alpha gene represented the most common cause of familial early-onse t (less than or equal to 40 years) diabetes: MODY3 (5.2%) more than MODY2 ( 3.5%) more than MIDD (2.6%) more than MODY1 (1.7%).