Human Molecular Genetics Advance Access originally published online on June 26, 2006
Human Molecular Genetics 2006 15(15):2363-2375; doi:10.1093/hmg/ddl161
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Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1ß/MODY5 mutations
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 and 3 Hopital Robert Debré, iUnité de Génétique Clinique, Paris, France
* To whom correspondence should be addressed. Tel: +33 144272151; Fax: +33 144273445; Email: silvia.cereghini{at}snv.jussieu.fr
Received April 3, 2006; Accepted June 21, 2006
Heterozygous mutations in the HNF1ß/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 exons 2 and 7 of HNF1ß, 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 HNF1ß carriers: bilateral enlarged polycystic kidneys, severe pancreas hypoplasia and abnormal genital tract. Consistent with this, we detected high levels of HNF1ß transcripts in 8-week human embryos in the mesonephros and metanephric kidney and in the epithelium of 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 the expression of ß-catenin and E-cadherin. 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 the Wnt/ß-catenin signaling pathway. Both fetuses exhibited a severe pancreatic hypoplasia with underdeveloped and disorganized acini, together with an absence of ventral pancreatic-derived tissue. ß-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 ß-cell maturation defect. This study provides evidence of differential gene-dosage requirements for HNF1ß in normal human kidney and pancreas differentiation and increases our understanding of the etiology of MODY5 disorder.
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