title: Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation.
abstract: One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT), a tolbutamide modified frequently sampled intravenous glucose tolerance test, and a glucagon test to examine for a possible early beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues.
authors.affiliation: Steno Diabetes Center and Hagendorn Research Institute, Copenhagen, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: H
authors.initials: H
authors.lastname: Eiberg
authors.forename: M
authors.initials: M
authors.lastname: Rouard
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: A M
authors.initials: AM
authors.lastname: Møller
authors.forename: S K
authors.initials: SK
authors.lastname: Rasmussen
authors.forename: M
authors.initials: M
authors.lastname: Fridberg
authors.forename: S A
authors.initials: SA
authors.lastname: Urhammer
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
authors.forename: K
authors.initials: K
authors.lastname: Almind
authors.forename: S M
authors.initials: SM
authors.lastname: Echwald
authors.forename: L
authors.initials: L
authors.lastname: Hansen
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005951:Glucose Tolerance Test; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D014044:Tolbutamide / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007004:Hypoglycemic Agents; D007328:Insulin; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D014044:Tolbutamide