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; Claire Carette; Jean-Pierre Riveline; René Valéro; Jean-François Gautier; Etienne Larger; Yves Reznik; Pierre-Henri Ducluzeau-Fieloux; Agnès Sola-Gazagnes; Agnès Hartemann-Heurtier; Pierre Lecomte; Lucy Chaillous; Marie Laloi-Michelin; Jean-Marie Wilhem; Pierre Cuny; Françoise Duron; Bruno Guerci; Nathalie Jeandidier; Helen Mosnier-Pudar; Michel Assayag; Danièle Dubois-Laforgue; Gilberto Velho; José Timsit

doi:10.2337/db07-0859

Article dans une revue

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

1 CHU Saint-Antoine [AP-HP]

2 IC UM3 (UMR 8104 / U1016) - Institut Cochin

3 CRC - Centre de Recherche des Cordeliers

4 Department of diabetes and endocrinology

5 Service Nutrition, Maladies Metaboliques, Endocrinologie

6 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers

7 Angiogénèse embryonnaire et pathologique

CIRB - Centre interdisciplinaire de recherche en biologie, INSERM - Institut National de la Santé et de la Recherche Médicale : U833, UPMC - Université Pierre et Marie Curie - Paris 6

8 UPD5 - Université Paris Descartes - Paris 5

9 Unité sous contrat aromatase et oestrogènes dans les gonades des mammifères

10 CHU - Centre Hospitalier Universitaire

11 SOPAM - Stress Oxydant et Pathologies Métaboliques

12 Université de Liège

13 IECM - Immuno-Endocrinologie Cellulaire et Moléculaire

14 Clinique d'endocrinologie

15 Hôpital Lariboisière-Fernand-Widal [APHP]

16 UHP - Université Henri Poincaré - Nancy 1

17 Service de Diabétologie, Nutrition et Maladies métaboliques [CHRU Nancy]

18 CHU Strasbourg

19 DIATHEC - Diabète et thérapeutique : îlots pancréatiques et innovations technologiques

20 USPC - Université Sorbonne Paris Cité

21 Service de diabétologie [CHU Cochin]

22 Hôpital Cochin [AP-HP]

23 (U 695) - Déterminants génétiques du diabète de type 2 et de ses complications vasculaires

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.

Keywords : hepatocyte nuclear factor 1-α MODY HNF1A maturity-onset diabetes of the young

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Article dans une revue

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Sciences du Vivant [q-bio]

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https://hal.univ-angers.fr/hal-03275383
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Soumis le : jeudi 1 juillet 2021 - 09:24:38
Dernière modification le : mercredi 27 avril 2022 - 03:42:38

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

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