title: Identification of three new mutations of the HNF-1 alpha gene in Japanese MODY families.
abstract: OBJECTIVE
  We analysed Japanese MODY patients for mutations in the HNF-1 alpha gene.
  
  
  METHODS
  Fifty unrelated Japanese patients with early-onset diabetes (diagnosed at 25 years of age or younger) or with a strong family history of diabetes were screened for mutations in the HNF-1 alpha gene. Functional studies of the mutant HNF-1alpha were carried out.
  
  
  RESULTS
  We identified three new mutations in the HNF-1 alpha gene in the families with a strong family history for diabetes. One mutation (L518P519fsTCC --> A) was identified in three unrelated families, while the other two mutations (T521I and V617I) were identified in one family. We also identified the A site of the promoter (+102G-to-C), which was reported previously. We examined the functional properties of the mutant HNF-1alpha. By increasing the amount of L518P519fsTCC-->A-HNF-1alpha, increasing inhibition of the transcription of human transthyretin (TTR) was observed (up to 61% of the control). Increasing amounts of T521I-HNF-1alpha or V617I-HNF-1alpha mutant proteins increased TTR promoter transcription up to 4.3-fold and 2.4-fold, respectively, whereas both increased transcription up to 12.4-fold of the control.
  
  
  CONCLUSIONS
  The L518P519fsTCC --> A was identified for the first time and this mutation might be a common cause of Japanese MODY3 in Okinawa area. In addition, both the T521I and V617I mutations were present in two patients in the same family. Since the prevalence of these mutations is relatively high (10%, 5/50), the HNF-1 alpha gene needs to be screened for mutations in patients either with early-onset diabetes or with a strong family history for diabetes.
authors.affiliation: Second Department of Internal Medicine, University of the Ryukyus School of Medicine, Nishihara, Okinawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ikema
authors.forename: Y
authors.initials: Y
authors.lastname: Shimajiri
authors.forename: I
authors.initials: I
authors.lastname: Komiya
authors.forename: M
authors.initials: M
authors.lastname: Tawata
authors.forename: S
authors.initials: S
authors.lastname: Sunakawa
authors.forename: H
authors.initials: H
authors.lastname: Yogi
authors.forename: M
authors.initials: M
authors.lastname: Shimabukuro
authors.forename: N
authors.initials: N
authors.lastname: Takasu
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D003545:Cysteine; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D005998:Glycine; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: 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; D003545:Cysteine; D005998:Glycine