Genetic variation in the hepatocyte nuclear factor-3 beta gene (HNF3B) does not contribute to maturity-onset diabetes of the young in French Caucasians

Mutations in genes encoding hepatocyte nuclear factor (HNF) are responsible for three of the five subtypes of maturity-onset diabetes of the young (MO DY). This observation and molecular studies indicate that the HNF network i s required for normal function of pancreatic beta-cells. This suggests that transcription factors involved in this complex network are candidates for genetic defects in MODY. Because the HNF-3 beta gene is implicated in this network, we screened it for mutations in 21 probands of French ancestry wit h clinical diagnosis of MODY and early-onset type 2 diabetes, All of the fi ve known MODY genes, HNF-4 alpha, glucokinase, HNF-1 alpha; HNF-1 beta, and IPF1, were previously excluded as being the cause of diabetes in these fam ilies, By direct sequencing, we identified two transitions, an A-to-G rat p osition -213 and a C-to-T at position -63 in the promoter and exon 1, respe ctively, of the HNF-3 beta gene. A G-to-C transversion at position +32 in t he intron 1 and three transitions, C-to-T at position 291, A to-G at positi on 837, and G-to-A at position 1188 in the exon 3, resulting in noncoding m utations Ala97Ala, Gly279Gly, and Gln396Gln, respectively, were also identi fied. The allele frequencies were not significantly different between a con trol group and MODY probands, Familial segregation studies and linkage anal ysis showed that; genetic variation in the HNF-3 beta gene is unlikely to b e the cause of early-onset type 2 diabetes in these Caucasian families.