title: A rapid screening method for hepatocyte nuclear factor 1 alpha frameshift mutations; prevalence in maturity-onset diabetes of the young and late-onset non-insulin dependent diabetes.
abstract: Non-insulin dependent diabetes (NIDDM) is a polygenic heterogeneous disorder of glucose homeostasis. Maturity-onset diabetes of the young (MODY) is a monogenic subtype of NIDDM characterised by early-onset (< 25 years) and autosomal dominant inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1 alpha) gene have recently been shown to cause MODY. The incidence of mutations in this gene in MODY and late-onset NIDDM is not known. We have developed a rapid specific polymerase chain reaction test for HNF-1 alpha mutations; this test involves the use of fluorescently labelled forward primers and modified reverse primers to detect length polymorphisms resulting from frameshift mutations. With this method, we have screened 102 MODY probands, viz. 60 defined according to strict diagnostic criteria (autosomal dominant inheritance and at least one member diagnosed age < 25 years) and 95 late-onset NIDDM probands (diagnosed 35-70 years with > or = 1 affected relative), for the presence of 9 known HNF-1 alpha frameshift mutations, including 6 that occur at two sites for recurring mutation (residues 291/292 and 379). Mutations were detected in 11 of the strictly defined MODY probands and one mutation was also found in a single subject with early-onset NIDDM but no family history of the disease. The HNF-1 alpha frameshift mutations were not detected in any late-onset NIDDM subjects, suggesting these mutations do not have a major role in the pathogenesis of NIDDM. Our results indicate that the prevalence of the nine frameshift mutations in strictly defined UK MODY is 18%, with the P291fsinsC mutation alone having a frequency of 13%.
authors.affiliation: Division of Molecular Genetics, University of Exeter, UK.
authors.forename: T M
authors.initials: TM
authors.lastname: Frayling
authors.forename: M P
authors.initials: MP
authors.lastname: Bulman
authors.forename: M
authors.initials: M
authors.lastname: Appleton
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: S
authors.initials: S
authors.lastname: Ellard
mesh_terms: D000328:Adult; D000368:Aged; D017931:DNA Primers; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000145:classification / Q000209:etiology / Q000235:genetics*; D016368:Frameshift Mutation; D005787:Gene Frequency; D005820:Genetic Testing / Q000379:methods*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics*; D006113:United Kingdom
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; 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