title: Detection and characterization of two novel mutations in the HNF4A gene in maturity-onset diabetes of the young type 1 in two Japanese families.
abstract: BACKGROUND
  Maturity-onset diabetes of the young (MODY) is a subgroup of monogenic diabetes mellitus, of which MODY1, caused by HNF4A mutations, accounts for only 5% or less and has been rarely reported in East Asian countries. Here we report two novel HNF4A mutations in two Japanese families with MODY1.
  
  
  METHODS
  Proband 1 is an 8-year-old girl and proband 2 is a 14-year-old girl. Both were nonobese, demonstrated elevated HbA1c and negative serum anti-glutamic acid decarboxylase antibodies, and had a family history of diabetes. We directly sequenced HNF4A and performed functional analysis of the detected missense mutation.
  
  
  RESULTS
  Proband 1 had a heterozygous missense mutation, c.824A>G (p.Asn275Ser). Luciferase assay demonstrated a significant reduction in transcriptional activity. A heterozygous frame shift mutation, c.692-695delAGGA (p.Lys231ThrfsX5), was detected in proband 2. Affected family members shared the same mutations, showing high penetrance. Both mutations reside in the HNF4α dimerization domain and the corresponding amino acids are well conserved between species.
  
  
  CONCLUSIONS
  These two mutations are most likely the cause of MODY1 in these families. Considering the effectiveness of sulfonylureas, it is important to correctly diagnose MODY1.
authors: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Makoto
authors: M
authors: Fujiwara
authors: Noriyuki
authors: N
authors: Namba
authors: Kohji
authors: K
authors: Miura
authors: Taichi
authors: T
authors: Kitaoka
authors: Haruhiko
authors: H
authors: Hirai
authors: Hiroki
authors: H
authors: Kondou
authors: Tsunesuke
authors: T
authors: Shimotsuji
authors: Chikahiko
authors: C
authors: Numakura
authors: Keiichi
authors: K
authors: Ozono
mesh_terms: D000293:Adolescent; D044466:Asian People / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D006367:HeLa Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D001786:Blood Glucose; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4