title: The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3.
abstract: OBJECTIVE
  The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-alpha (HNF1A) gene mutation.
  
  
  METHODS
  We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes.
  
  
  RESULTS
  Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10(-4)). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03).
  
  
  CONCLUSIONS
  These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.
authors.affiliation: Département de Génétique, Groupe Hospitalier Pitié-Salpétrière, Bât 6 rue Lapeyronie, 47/83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France. christine.bellanne-chantelot@psl.aphp.fr
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Claire
authors.initials: C
authors.lastname: Carette
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Riveline
authors.forename: René
authors.initials: R
authors.lastname: Valéro
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.forename: Etienne
authors.initials: E
authors.lastname: Larger
authors.forename: Yves
authors.initials: Y
authors.lastname: Reznik
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Ducluzeau
authors.forename: Agnès
authors.initials: A
authors.lastname: Sola
authors.forename: Agnès
authors.initials: A
authors.lastname: Hartemann-Heurtier
authors.forename: Pierre
authors.initials: P
authors.lastname: Lecomte
authors.forename: Lucy
authors.initials: L
authors.lastname: Chaillous
authors.forename: Marie
authors.initials: M
authors.lastname: Laloi-Michelin
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Wilhem
authors.forename: Pierre
authors.initials: P
authors.lastname: Cuny
authors.forename: Françoise
authors.initials: F
authors.lastname: Duron
authors.forename: Bruno
authors.initials: B
authors.lastname: Guerci
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jeandidier
authors.forename: Helen
authors.initials: H
authors.lastname: Mosnier-Pudar
authors.forename: Michel
authors.initials: M
authors.lastname: Assayag
authors.forename: Danièle
authors.initials: D
authors.lastname: Dubois-Laforgue
authors.forename: Gilberto
authors.initials: G
authors.lastname: Velho
authors.forename: José
authors.initials: J
authors.lastname: Timsit
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D014644:Genetic Variation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D017384:Sequence Deletion
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha