title: Early-onset Type II diabetes mellitus in Italian families due to mutations in the genes encoding hepatic nuclear factor 1 alpha and glucokinase.
abstract: OBJECTIVE
  Maturity-onset-diabetes of the young (MODY) is caused by mutations in at least five different genes. Our aim was to determine the prevalence of the most common MODY genes in Italian families with early-onset Type II (non-insulin-dependent) diabetes mellitus.
  
  
  METHODS
  We screened 28 Italian early-onset Type II diabetic families (diagnosis < 35 years) for mutations in the hepatic nuclear factor-4 alpha, (MODY1), glucokinase (MODY2) and hepatic nuclear factor-1 alpha (MODY3). Both strands of exons, flanking introns and minimal promoter regions of the above-mentioned genes were amplified using polymerase chain reaction and were sequenced directly.
  
  
  RESULTS
  We identified four different mutations, three of which are not described, (W113X, G42P43fsCC --> A, H514R) and four new polymorphisms (G184G, T513T, IVS3-nt47delG, IVS1- nt53C --> G) in the hepatic nuclear factor-1 alpha gene, two new potential mutations (G44S, IVS4nt + 7C --> T) and three new polymorphisms (promoter-nt84C --> G, IVS9 + nt8C --> T, IVS9 + nt49G --> A) in the glucokinase gene, and a new polymorphism (IVS1c-nt11T --> G) in the hepatic nuclear factor-4 alpha gene.
  
  
  CONCLUSIONS
  Mutations in the hepatic nuclear factor-1 alpha and glucokinase are associated with Type II diabetes in 14 % and 7 % of Italian families, respectively. Our findings provide an impetus for screening Italian MODY and early-non Type II diabetic families for mutations in the above mentioned genes to identify relatives at risk who could benefit from primary prevention care. [
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biology and Medicine, University of Chicago, Chicago, Illinois, USA. cgragnoli@partners.org
authors.forename: C
authors.initials: C
authors.lastname: Gragnoli
authors.forename: B N
authors.initials: BN
authors.lastname: Cockburn
authors.forename: F
authors.initials: F
authors.lastname: Chiaramonte
authors.forename: A
authors.initials: A
authors.lastname: Gorini
authors.forename: G
authors.initials: G
authors.lastname: Marietti
authors.forename: G
authors.initials: G
authors.lastname: Marozzi
authors.forename: A M
authors.initials: AM
authors.lastname: Signorini
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007328:Insulin / Q000097:blood; D007558:Italy; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; 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; D007328:Insulin; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005941:Glucokinase