Clinical Spectrum Associated with Hepatocyte Nuclear Factor-1β Mutations

Clinical Spectrum Associated with Hepatocyte Nuclear Factor-1β Mutations

Christine Bellanné-Chantelot, PharmD, PhD;
Dominique Chauveau, MD;
Jean-François Gautier, MD, PhD;
Danièle Dubois-Laforgue, MD, PhD;
Séverine Clauin;
Sandrine Beaufils;
Jean-Marie Wilhelm, MD;
Christian Boitard, MD;
Laure-Hélène Noël, MD;
Gilberto Velho, MD, PhD; and
José Timsit, MD

From Hôpital Saint-Antoine, Hôpital Cochin, Hôpital Necker, Hôpital Saint-Louis, and Hôpital Saint-Vincent-de-Paul, Paris, France, and Hôpital Saint-Morand, Altkirch, France.

Abstract

Background: Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1β (HNF-1β) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1β mutations.

Objective: To describe clinical and genetic findings in 13 patients with 8 novel HNF-1β mutations.

Design: Multicenter, descriptive study.

Setting: 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology.

Participants: 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring.

Measurements: Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results.

Results: All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients.

Limitations: Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1β mutations.

Conclusions: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1β is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.

Article and Author Information

Acknowledgments: The authors thank the families for their participation in the study; Drs. Véronique Baudouin, Véronique Blanchetier, Guy Parlier, and Rémi Salomon for the follow-up of patients; and Dr. Pascal Hammel for helpful advice.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Christine Bellanné-Chantelot, PharmD, PhD, Fédération des Services de Biochimie, Laboratoire de Biologie Moléculaire, Hôpital Saint-Antoine, 184 rue du faubourg Saint-Antoine, 75012 Paris, France; e-mail, christine.bellanne{at}sat.ap-hop-paris.fr.
Current Author Addresses: Dr. Bellanné-Chantelot, Ms. Clauin, and Ms. Beaufils: Fédération des Services de Biochimie, Laboratoire de Biologie Moléculaire, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France.
Drs. Chauveau and Noël: Service de Néphrologie, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France.
Dr. Gautier: Service d'Endocrinologie, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France.
Drs. Dubois-Laforgue, Boitard, and Timsit: Service d'Immuno-Diabétologie, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France.
Dr. Wilhelm: Centre Hospitalier Saint-Morand, BP 1022, 68134 Altkirch Cedex, France.
Dr. Velho: INSERM U561, Hôpital Saint-Vincent-de-Paul, 74 Avenue Denfert Rochereau, 75014, Paris, France.
Author Contributions: Conception and design: C. Bellanné-Chantelot, D. Chauveau, G. Velho, J. Timsit.
Analysis and interpretation of the data: C. Bellanné-Chantelot, D. Chauveau, J.-F. Gautier, D. Dubois-Laforgue, S. Clauin, S. Beaufils, J.-M. Wilhelm, C. Boitard, L.-H. Noël, G. Velho, J. Timsit.
Drafting of the article: C. Bellanné-Chantelot, D. Chauveau, G. Velho, J. Timsit.
Critical revision of the article for important intellectual content: C. Bellanné-Chantelot, D. Chauveau, J.-F. Gautier, D. Dubois-Laforgue, C. Boitard, G. Velho, J. Timsit.
Final approval of the article: C. Bellanné-Chantelot, D. Chauveau, J.-F. Gautier, D. Dubois-Laforgue, S. Clauin, S. Beaufils, J.-M. Wilhelm, C. Boitard, L.-H. Noël, G. Velho, J. Timsit.
Provision of study materials or patients: D. Chauveau, J.-F. Gautier, D. Dubois-Laforgue, J.-M. Wilhelm, C. Boitard, J. Timsit.
Administrative, technical, or logistic support: S. Clauin, S. Beaufils.
Collection and assembly of data: C. Bellanné-Chantelot, D. Chauveau, J. Timsit.