Genetic Variation in the Hepatocyte Nuclear F a c t o r-3 Gene (H N F 3 B) Does Not Contribute to Maturity-Onset Diabetes of the Young in French C a u c a s i a n s

Mutations in genes encoding hepatocyte nuclear factor (HNF) are responsible for three of the five subtypes of maturity-onset diabetes of the young (MODY). This observation and molecular studies indicate that the HNF network is required for normal function of pancreatic -cells. This suggests that transcription factors involved in this complex network are candidates for genetic defects in MODY. Because the H N F - 3 gene is implicated in this network, we screened it for mutations in 21 probands of French ancestry with clinical diagnosis of MODY and early-onset type 2 diabetes. All of the five known MODY genes, H N F - 4 , g l u c o k i n a s e, H N F - 1 , H N F - 1 , and I P F 1, were previously excluded as being the cause of diabetes in these families. By direct sequencing, we identified two transitions, an A-to-G at position ‐213 and a C-to-T at position ‐63 in the promoter and exon 1, respectively, of the H N F - 3 gene. A G-to-C transversion at position +32 in the intron 1 and three transitions, C-to-T at position 291, A-to-G at position 837, and G-to-A at position 1188 in the exon 3, resulting in noncoding mutations Ala97Ala, Gly279Gly, and Gln396Gln, respectively, were also identified. The allele frequencies were not significantly diff e r e n t between a control group and MODY probands. Familial segregation studies and linkage analysis showed that genetic variation in the H N F - 3 gene is unlikely to be the cause of early-onset type 2 diabetes in these Caucasian families. Diabetes 4 9 :3 0 6‐308, 2000