title: Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3).
abstract: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. Recent studies have shown that mutations in the two functionally related transcription factors, hepatocyte nuclear factor 4 alpha (HNF-4alpha) and hepatocyte nuclear factor 1 alpha (HNF-1alpha) are associated with the MODY1 and MODY3 forms of diabetes respectively, whereas mutations in the enzyme glucokinase are the cause of the MODY2 form. We have examined 10 unrelated Caucasian families in which MODY/NIDDM co-segregated with markers for MODY3 for mutations in the HNF-1alpha gene (TCF1). Ten different mutations were observed in these families, all of which co-segregated with diabetes. There were no obvious relationships between the nature of the mutations observed (i.e. frameshift, nonsense, or missense) or their location in the gene with clinical features of diabetes (age at onset, severity) in these families. The mechanisms by which mutations in the HNF-1alpha gene cause diabetes mellitus are unclear but might include abnormal pancreatic islet development during foetal life thereby limiting their later function, as well as impaired transcriptional regulation of genes that play a key role in normal pancreatic beta cell function.
authors.affiliation: CNRS EP10, Institut Pasteur de Lille & CHU de Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: M
authors.initials: M
authors.lastname: Rouard
authors.forename: K
authors.initials: K
authors.lastname: Yamagata
authors.forename: N
authors.initials: N
authors.lastname: Oda
authors.forename: P J
authors.initials: PJ
authors.lastname: Kaisaki
authors.forename: V V
authors.initials: VV
authors.lastname: Boriraj
authors.forename: J C
authors.initials: JC
authors.lastname: Chevre
authors.forename: V
authors.initials: V
authors.lastname: Boccio
authors.forename: R D
authors.initials: RD
authors.lastname: Cox
authors.forename: G M
authors.initials: GM
authors.lastname: Lathrop
authors.forename: P
authors.initials: P
authors.lastname: Dussoix
authors.forename: J
authors.initials: J
authors.lastname: Philippe
authors.forename: J
authors.initials: J
authors.lastname: Timsit
authors.forename: G
authors.initials: G
authors.lastname: Charpentier
authors.forename: G
authors.initials: G
authors.lastname: Velho
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
authors.forename: P
authors.initials: P
authors.lastname: Froguel
mesh_terms: D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D044465:White People
chemical_list: D004268:DNA-Binding Proteins; D005819:Genetic Markers; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta