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Published online November 14, 2007
Diabetes 57:503-508, 2008
DOI: 10.2337/db07-0859
© 2008 by the American Diabetes Association
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Brief Report

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-Chantelot1, Claire Carette2, Jean-Pierre Riveline3, René Valéro4, Jean-François Gautier5, Etienne Larger6,9, Yves Reznik7, Pierre-Henri Ducluzeau8, Agnès Sola9, Agnès Hartemann-Heurtier10, Pierre Lecomte11, Lucy Chaillous12, Marie Laloi-Michelin13, Jean-Marie Wilhem14, Pierre Cuny15, Françoise Duron16, Bruno Guerci17, Nathalie Jeandidier18, Helen Mosnier-Pudar19, Michel Assayag20, Danièle Dubois-Laforgue2, Gilberto Velho21, and José Timsit2

1 Department of Genetics, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
2 Department of Immunology and Diabetology, AP-HP Hôpital Cochin, Université René Descartes- Paris5, and Inserm, Research Unit 561, Paris, France
3 Department of Endocrinology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France
4 Department of Nutrition-Metabolic Diseases-Endocrinology, AP-HM CHU de la Timone, Marseille, France
5 Department of Endocrinology, AP-HP Hôpital Saint-Louis, Université Denis Diderot-Paris7, Paris, France
6 Department of Diabetology, AP-HP Hôpital Bichat, Paris, France
7 Department of Endocrinology, CHU Caen, Caen, France
8 Department of Endocrinology, CHU Angers, Angers, France
9 Department of Diabetology, AP-HP Hôpital Hôtel Dieu, Paris, France
10 Department of Diabetology, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris6, Paris, France
11 Department of Endocrinology, CHU Bretonneau, Tours, France
12 Department of Endocrinology, CHU Nantes, Nantes, France
13 Department of Internal Medicine, AP-HP Hôpital Lariboisière, Paris, France
14 Department of Internal Medicine, Centre Hospitalier Saint-Morand, Altkirch, France
15 Department of Diabetology, Hôpital Beauregard, Thionville, France
16 Department of Endocrinology, AP-HP Hôpital Saint-Antoine, Paris, France
17 Department of Diabetology, CHU Nancy, Nancy, France
18 Department of Diabetology, CHU Strasbourg, Strasbourg, France
19 Department of Endocrinology, AP-HP Hôpital Cochin, Université Paris 5, Paris, France
20 Department of Internal Medicine, Centre Hospitalier Compiègne, Compiègne, France
21 Inserm, Research Unit 695, Paris, France

Address correspondence and reprint requests to Christine Bellanné-Chantelot, Département de Génétique, Groupe Hospitalier Pitié-Salpétrière, Bât 6 rue Lapeyronie, 47/83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: christine.bellanne-chantelot{at}psl.aphp.fr

Key Words: HNF1A, hepatocyte nuclear factor 1-{alpha} • MODY, maturity-onset diabetes of the young

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.

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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