Studies of the variability of the hepatocyte nuclear factor-1β (HNF-1β / TCF2) and the dimerization cofactor of HNF-1 (DcoH / PCBD) genes in relation to type 2 diabetes mellitus and β-cell function

✍ Scribed by Jakob Ek; Niels Grarup; Søren A. Urhammer; Peter H. Gæde; Thomas Drivsholm; Knut Borch-Johnsen; Torben Hansen; Oluf Pedersen

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 41 KB
• Volume: 18
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.1201

✦ Synopsis

Communicated by Haig Kazazian

Mutations in the homeodomain-containing transcription factor hepatocyte nuclear factor-1 β β (HNF-1 β β ) are known to cause a rare subtype of maturity-onset diabetes of the young (MODY5), which is associated with early-onset progressive non-diabetic renal dysfunction. To investigate whether mutations in HNF-1 β β are implicated in the pathogenesis of MODY or late-onset diabetes with and without nephropathy in Danish Caucasians we examined the HNF-1 β β (TCF2) and the dimerization cofactor of HNF-1 (DCoH, PCBD) genes for mutations in 11 MODY probands, 28 type 2 diabetic patients with nephropathy, and 46 type 2 diabetic patients with an impaired β β -cell function by combined single-strand conformation polymorphism (SSCP) and heteroduplex analysis. Analysis of the promoter and nine exons including intron-exon boundaries of the HNF-1 β β gene revealed one novel silent polymorphism and three previously reported intronic variants. The silent polymorphism (I91I) was found in one patient with late-onset type 2 diabetes. One of the intronic variant (IVS6+26T→ → C) was examined further. Among 584 type 2 diabetic patients the allelic frequency was 13.1% (11.2-15.0%) compared to 11.6% (8.6-14.5%) in 229 glucose tolerant control subjects (NS). No difference in insulin secretion during an OGTT was seen between carriers of the different IVS6+26T→ → C genotypes among the 229 middle-aged control subjects, nor among 302 glucose tolerant 60-year-old Danish Caucasians. Mutation analysis of the four exons comprising the DCoH gene revealed a previously described A → → G polymorphism located in the 3' untranslated region, which was not investigated further. In conclusion, mutations in HNF-1 β β and DCoH are not a major cause of MODY or late onset type 2 diabetes in Danish Caucasian subjects.