![]() |
Christine Bellanné-Chantelot 1
Auteur
Claire Carette 2
Auteur
Jean-Pierre Riveline 3, 4
Auteur
René Valéro 5
Auteur
Jean-François Gautier 6
Auteur
Etienne Larger 7, 8
Auteur
Yves Reznik 9, 10
Auteur
Pierre-Henri Ducluzeau-Fieloux 11
Auteur IdHAL : pierre-henri-ducluzeau
Agnès Sola-Gazagnes
Auteur
Agnès Hartemann-Heurtier
Auteur
Pierre Lecomte 12
Auteur
Lucy Chaillous 13, 14
Auteur
Marie Laloi-Michelin 15
Auteur
Jean-Marie Wilhem
Auteur
Pierre Cuny 16
Auteur
Françoise Duron
Auteur
Bruno Guerci 17
Auteur
Nathalie Jeandidier 18, 19
Auteur
Helen Mosnier-Pudar
Auteur
Michel Assayag
Auteur
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-α (HNF1A) gene mutation.
RESEARCH DESIGN AND 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.
UNIV-ANGERS | CDF | ESPCI | INRA | PSL | CORDELIERS | ENS-PARIS | UNIV-PARIS5 | UNIV-LORRAINE | UNIV-NANTES | UNICAEN | EPHE | CNRS | INRAE | SITE-ALSACE | UP-SANTE | COMUE-NORMANDIE | SU-SCIENCES | UPMC | ESPCI-PSL | UNIV-PARIS7 | UNIV-PARIS | PARISTECH | SORBONNE-UNIVERSITE | SU-MEDECINE