title: Studies of the variability of the hepatocyte nuclear factor-1beta (HNF-1beta / TCF2) and the dimerization cofactor of HNF-1 (DcoH / PCBD) genes in relation to type 2 diabetes mellitus and beta-cell function.
abstract: Mutations in the homeodomain-containing transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) 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 are implicated in the pathogenesis of MODY or late-onset diabetes with and without nephropathy in Danish Caucasians we examined the HNF-1beta (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 beta-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-1beta 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-1beta and DCoH are not a major cause of MODY or late onset type 2 diabetes in Danish Caucasian subjects.
authors.affiliation: Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Copenhagen, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Ek
authors.forename: N
authors.initials: N
authors.lastname: Grarup
authors.forename: S A
authors.initials: SA
authors.lastname: Urhammer
authors.forename: P H
authors.initials: PH
authors.lastname: Gaede
authors.forename: T
authors.initials: T
authors.lastname: Drivsholm
authors.forename: K
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000097:blood / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005951:Glucose Tolerance Test; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007438:Introns / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496495:HNF1B protein, human; D007328:Insulin; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta; D006836:Hydro-Lyases; C076392:pterin-4a-carbinolamine dehydratase