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Human Molecular Genetics Advance Access published online on June 26, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl161
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received April 3, 2006
Revised June 21, 2006
Accepted June 21, 2006

Article

Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations

Cécile Haumaitre 1, Mélanie Fabre 1, Sarah Cormier 2, Clarisse Baumann 3, Anne-Lise Delezoide 2, and Silvia Cereghini 1 *

1 Laboratoire de Biologie du développement, Unité Mixte de Recherche 7622, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, Paris, France
2 Hopital Robert Debré, Service de foetopathologie, Paris, France
3 Hopital Robert Debré, Unité de Génétique Clinique, Paris, France

* To whom correspondence should be addressed.
Silvia Cereghini, E-mail: Silvia.Cereghini{at}snv.jussieu.fr


  Abstract

Heterozygous mutations in the HNF1beta/vHNF1/TCF2 gene cause Maturity-Onset Diabetes of the Young (MODY5), associated with severe renal disease and abnormal genital tract. Here, we characterize two fetuses, a 27-week male and a 31.5-week female, carrying novel mutations in HNF1beta exons 2 and 7, respectively. Although these mutations were predicted to have different functional consequences, both fetuses displayed highly similar phenotypes. They presented one of the most severe phenotypes described in HNF1beta-carriers: bilateral enlarged polycystic kidneys, severe pancreas hypoplasia and abnormal genital tract. Consistent with this, we detected high levels of HNF1{beta}eta transcripts in 8-weeks human embryos in the mesonephros and metanephric kidney as well as in the epithelium of the pancreas. Renal histology and immunohistochemistry analyses of mutant fetuses revealed cysts derived from all nephron-segments with multilayered epithelia and dysplastic regions, accompanied by a marked increase in beta-catenin and E-cadherin expression. A significant proportion of cysts still expressed the cystic renal disease proteins, Polycystin-1, Polycystin-2, Fibrocystin and Uromodulin, implying that cyst formation may result from a deregulation of cell-cell adhesion and/or Wnt/beta - catenin signaling pathway. Both fetuses exhibited a severe pancreatic hypoplasia with underdeveloped and disorganized acini, together with an absence of ventral pancreatic-derived tissue. Beta-catenin and E-cadherin were strongly downregulated in the exocrine and endocrine compartments, and the islets lacked the transporter essential for glucose-sensing GLUT2, indicating a beta-cell maturation defect. This study provides evidence of differential gene-dosage requirements for HNF1beta in normal human kidney and pancreas differentiation and increases our understanding in the etiology of MODY5 disorder.


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