Mutation screening of the neurogenin-3 gene in autosomal dominant diabetes

We investigated whether genetic variability in neurogenin-3, a basic helix- loop-helix transcription factor that is expressed in the developing pancrea s, contributes to the etiology of maturity-onset diabetes of the young or o ther forms of autosomal dominant diabetes. Ninety-one probands of families with autosomal dominant diabetes were screened for neurogenin-3 mutations b y dideoxy fingerprinting. Three sequence differences were identified: a pol ymorphism not affecting the amino acid sequence (L75L), a CA insertion/dele tion in intron 1 (-44ins/del), and a C to T transition causing a serine to phenylalanine substitution (S199F). None of these sequence differences were more frequent in the family probands than in 179 nondiabetic controls. In contrast, allele 199F was weakly, but significantly, associated with common type 2 diabetes (199F frequencies = 0.436 in 132 cases with type 2 diabete s us. 0.346 in the family probands and 0.346 in controls; P = 0.05). The re lative risk of type 2 diabetes for 199F carriers was 1.7 (95% confidence in terval, 1.04-2.7). We conclude that sequence differences in the neurogenin- 3 gene do not play a major role in the development of autosomal dominant di abetes. Rather, they might contribute to common type 2 diabetes, although t his finding must be replicated in other populations.