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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

Christine Bellanné-Chantelot 1 Claire Carette 2 Jean-Pierre Riveline 3, 4 René Valéro 5 Jean-François Gautier 6 Etienne Larger 7, 8 Yves Reznik 9, 10 Pierre-Henri Ducluzeau-Fieloux 11 Agnès Sola-Gazagnes Agnès Hartemann-Heurtier Pierre Lecomte 12 Lucy Chaillous 13, 14 Marie Laloi-Michelin 15 Jean-Marie Wilhem Pierre Cuny 16 Françoise Duron Bruno Guerci 17 Nathalie Jeandidier 18, 19 Helen Mosnier-Pudar Michel Assayag Danièle Dubois-Laforgue 20, 2, 21, 8, 22 Gilberto Velho 23 José Timsit 21
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-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.

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https://hal.univ-angers.fr/hal-03275383
Contributeur : Okina Université d'Angers <>
Soumis le : jeudi 1 juillet 2021 - 09:24:38
Dernière modification le : mardi 13 juillet 2021 - 03:26:51

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Christine Bellanné-Chantelot, Claire Carette, Jean-Pierre Riveline, René Valéro, Jean-François Gautier, et al.. 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. Diabetes, American Diabetes Association, 2008, 57 (2), pp.503 - 508. ⟨10.2337/db07-0859⟩. ⟨hal-03275383⟩

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