Article    Table of Contents                    Full Text of this article    PDF of this article (PDFs free after 6 months)    Summary for Patients    Summary for Patients (PDF)    Figures/Tables List    Related articles in Annals  Services    Send comment/rapid response letter    Notify a friend about this article    Alert me when this article is cited    Add to Personal Archive    Download to Citation Manager    ACP Search                            Get Permissions  Google Scholar    Search for Related Content  PubMed Articles in PubMed by Author:    Bellanné-Chantelot, C.    Timsit, J.    Related Articles in PubMed    PubMed Citation    PubMed

ARTICLE

Clinical Spectrum Associated with Hepatocyte Nuclear Factor-1ß 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

6 April 2004 | Volume 140 Issue 7 | Pages 510-517

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-1ß (HNF-1ß) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1ß mutations.

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

Conclusions: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1ß 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.

Editors' Notes Context Maturity-onset diabetes of the young type 5 (MODY5) is an uncommon variant of a dominantly inherited disease associated with mutations in the hepatocyte nuclear factor-1ß (HNF-1ß) gene. We know little about its spectrum except that it may include urogenital abnormalities. Contribution This multicenter study describes 8 probands with MODY5 and known nondiabetic kidney disease and 5 offspring. Each proband had a different mutation in the HNF-1ß gene. Probands and offspring had various renal abnormalities, including dysplastic kidneys and renal cysts. Some also had genital tract abnormalities, pancreatic atrophy, and abnormal liver enzyme levels. Implications Maturity-onset diabetes of the young type 5 is genetically and phenotypically heterogeneous. –The Editors

 

Author and Article Information

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.

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.

Related articles in Annals:

Summaries for Patients
Maturity Onset Diabetes of the Young 5

Annals 2004 140: I-42. [Full Text]  

This article has been cited by other articles:

				P. J. Murray, K. Thomas, C. J. Mulgrew, S. Ellard, E. L. Edghill, and C. Bingham Whole gene deletion of the hepatocyte nuclear factor-1{beta} gene in a patient with the prune-belly syndrome Nephrol. Dial. Transplant., July 1, 2008; 23(7): 2412 - 2415. [Full Text] [PDF]

				M. Vaxillaire and P. Froguel Monogenic Diabetes in the Young, Pharmacogenetics and Relevance to Multifactorial Forms of Type 2 Diabetes Endocr. Rev., May 1, 2008; 29(3): 254 - 264. [Abstract] [Full Text] [PDF]

				L. Aguilar-Bryan and J. Bryan Neonatal Diabetes Mellitus Endocr. Rev., May 1, 2008; 29(3): 265 - 291. [Abstract] [Full Text] [PDF]

				E. L. Edghill, R. A. Oram, M. Owens, K. L. Stals, L. W. Harries, A. T. Hattersley, S. Ellard, and C. Bingham Hepatocyte nuclear factor-1{beta} gene deletions--a common cause of renal disease Nephrol. Dial. Transplant., February 1, 2008; 23(2): 627 - 635. [Abstract] [Full Text] [PDF]

				M. Vesterhus, H. Raeder, S. Johansson, A. Molven, and P. R. Njolstad Pancreatic Exocrine Dysfunction in Maturity-Onset Diabetes of the Young Type 3 Diabetes Care, February 1, 2008; 31(2): 306 - 310. [Abstract] [Full Text] [PDF]

				Z. Ma, Y. Gong, V. Patel, C. M. Karner, E. Fischer, T. Hiesberger, T. J. Carroll, M. Pontoglio, and P. Igarashi Mutations of HNF-1 inhibit epithelial morphogenesis through dysregulation of SOCS-3 PNAS, December 18, 2007; 104(51): 20386 - 20391. [Abstract] [Full Text] [PDF]

				C. Carette, C. Vaury, A. Barthelemy, S. Clauin, J.-P. Grunfeld, J. Timsit, and C. Bellanne-Chantelot Exonic Duplication of the Hepatocyte Nuclear Factor-1{beta} Gene (Transcription Factor 2, Hepatic) as a Cause of Maturity Onset Diabetes of the Young Type 5 J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2844 - 2847. [Abstract] [Full Text] [PDF]

				S. Hegde, C. Wright, M. Shenoy, N. E Moghal, and M. G Coulthard Renovascular hypertension commencing during fetal life Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2007; 92(4): F301 - F304. [Abstract] [Full Text] [PDF]

				B. Karges, C. Bergmann, K. Scholl, E. Heinze, F. M. Rasche, K. Zerres, K.-M. Debatin, M. Wabitsch, and W. Karges Digenic Inheritance of Hepatocyte Nuclear Factor-1{alpha} and -1{beta} With Maturity-Onset Diabetes of the Young, Polycystic Thyroid, and Urogenital Malformations Diabetes Care, June 1, 2007; 30(6): 1613 - 1614. [Full Text] [PDF]

				M. Vaxillaire, A. Dechaume, K. Busiah, H. Cave, S. Pereira, R. Scharfmann, G. P. de Nanclares, L. Castano, P. Froguel, M. Polak, et al. New ABCC8 Mutations in Relapsing Neonatal Diabetes and Clinical Features Diabetes, June 1, 2007; 56(6): 1737 - 1741. [Abstract] [Full Text] [PDF]

				S. Decramer, O. Parant, S. Beaufils, S. Clauin, C. Guillou, S. Kessler, J. Aziza, F. Bandin, J. P. Schanstra, and C. Bellanne-Chantelot Anomalies of the TCF2 Gene Are the Main Cause of Fetal Bilateral Hyperechogenic Kidneys J. Am. Soc. Nephrol., March 1, 2007; 18(3): 923 - 933. [Abstract] [Full Text] [PDF]

				S. Kitanaka, U. Sato, and T. Igarashi Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1{beta} and HNF-1{alpha} and the abnormality of HNF-1{beta} mutants J. Endocrinol., January 1, 2007; 192(1): 141 - 147. [Abstract] [Full Text] [PDF]

				C. Haumaitre, M. Fabre, S. Cormier, C. Baumann, A.-L. Delezoide, and S. Cereghini Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1{beta}/MODY5 mutations Hum. Mol. Genet., August 1, 2006; 15(15): 2363 - 2375. [Abstract] [Full Text] [PDF]

				A. T. Hattersley and E. R. Pearson Minireview: Pharmacogenetics and Beyond: The Interaction of Therapeutic Response, {beta}-Cell Physiology, and Genetics in Diabetes Endocrinology, June 1, 2006; 147(6): 2657 - 2663. [Abstract] [Full Text] [PDF]

				A. Brackenridge, E. R. Pearson, F. Shojaee-Moradie, A. T. Hattersley, D. Russell-Jones, and A. M. Umpleby Contrasting Insulin Sensitivity of Endogenous Glucose Production Rate in Subjects With Hepatocyte Nuclear Factor-1{beta} and -1{alpha} Mutations Diabetes, February 1, 2006; 55(2): 405 - 411. [Abstract] [Full Text] [PDF]

				T. Ulinski, S. Lescure, S. Beaufils, V. Guigonis, S. Decramer, D. Morin, S. Clauin, G. Deschenes, F. Bouissou, A. Bensman, et al. Renal Phenotypes Related to Hepatocyte Nuclear Factor-1beta (TCF2) Mutations in a Pediatric Cohort J. Am. Soc. Nephrol., February 1, 2006; 17(2): 497 - 503. [Abstract] [Full Text] [PDF]

				E L Edghill, C Bingham, S Ellard, and A T Hattersley Mutations in hepatocyte nuclear factor-1{beta} and their related phenotypes J. Med. Genet., January 1, 2006; 43(1): 84 - 90. [Abstract] [Full Text] [PDF]

				S. Rebouissou, V. Vasiliu, C. Thomas, C. Bellanne-Chantelot, H. Bui, Y. Chretien, J. Timsit, C. Rosty, P. Laurent-Puig, D. Chauveau, et al. Germline hepatocyte nuclear factor 1{alpha} and 1{beta} mutations in renal cell carcinomas Hum. Mol. Genet., March 1, 2005; 14(5): 603 - 614. [Abstract] [Full Text] [PDF]

				C. Haumaitre, E. Barbacci, M. Jenny, M. O. Ott, G. Gradwohl, and S. Cereghini Lack of TCF2/vHNF1 in mice leads to pancreas agenesis PNAS, February 1, 2005; 102(5): 1490 - 1495. [Abstract] [Full Text] [PDF]

				E. Barbacci, A. Chalkiadaki, C. Masdeu, C. Haumaitre, L. Lokmane, C. Loirat, S. Cloarec, I. Talianidis, C. Bellanne-Chantelot, and S. Cereghini HNF1{beta}/TCF2 mutations impair transactivation potential through altered co-regulator recruitment Hum. Mol. Genet., December 15, 2004; 13(24): 3139 - 3149. [Abstract] [Full Text] [PDF]

				E. Fischer, L. Gresh, A. Reimann, and M. Pontoglio Cystic kidney diseases: learning from animal models Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2700 - 2702. [Full Text] [PDF]