Missense mutations in the human insulin promoter factor-1 gene and their relation to maturity-onset diabetes of the young and late-onset type 2 diabetes mellitus in Caucasians

Increasing evidence suggests that defects in genes encoding transcription f actors that are expressed in the pancreatic p-cells may be important contri butors to the genetic basis of type 2 diabetes mellitus. Maturity-onset dia betes of the young (MODY) now exists in five subtypes (MODYL-5), four of wh ich are caused by mutations in transcription factors hepatocyte nuclear fac tor-4 alpha (HNF-4 alpha), HNF-1 alpha, insulin promoter factor-1 (IPF-1), and HNF-1 beta (MODY1, -3, -4, and -5). Recent evidence from the British po pulation even suggested that IPF-1 may be a predisposing gene for type 2 di abetes. Thus, highlighting the potential role of this transcription factor in the genetic basis of Danish and Italian MODY as well as in Danish patien ts with late-onset type 2 diabetes mellitus, we have examined the human IPF -1 gene for mutations by single strand conformation polymorphism and hetero duplex analysis in 200 Danish patients with late-onset type 2 diabetes and in 44 Danish and Italian MODY patients. In the patients with late-onset typ e 2 diabetes we identified a noncoding G insertion/deletion polymorphism at nucleotide - 108, a silent G54G, and a rare missense D76N variant. Moreove r, a Danish MODY patient was carrier of an A140T variant. Neither the D76N nor the A140T segregated with diabetes, and their transcriptional activatio n of the human insulin promoter expressed in vitro was indistinguishable fr om that of the wild type (115 +/- 21% and 84 +/- 12% us. 100%). We conclude that variants in IPF-1 are not a common cause of MODY or late-onset type 2 diabetes in the Caucasian population, and that in terms of insulin transcr iption both the N76 and the T140 mutations are likely to represent function ally normal IPF-1 variants with no direct role in the pathogenesis of MODY or late-onset type 2 diabetes mellitus.