Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1β/MODY5 mutations

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 exons 2 and 7 of HNF1beta, 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 HNF1beta 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 beta-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/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 of the etiology of MODY5 disorder.

The protein tyrosine phosphatase-BL, modulates pancreatic β-cell proliferation by interaction with the Wnt signalling pathway

“…There has been recent in vivo evidence that supports a role for the modulation of Wnt signalling by HNF1b. For example, in two foetuses with mutations in HNF1b, levels of b-catenin were found to be increased in the kidney, but decreased in the exocrine and endocrine pancreas (Haumaitre et al 2006). Our current study has implicated the multi-functional tyrosine phosphatase, PTP-BL, in mediating some of the effects of HNF1b and has revealed that PTP-BL may influence b-cell proliferation by regulating b-catenin levels.…”

Spectrum of HNF1B Mutations in a Large Cohort of Patients Who Harbor Renal Diseases

“…Renal manifestations are frequently observed in patients with maturity-onset diabetes of the young type 5 and include a wide spectrum of phenotypes (2). More recently, HNF1B mutations were found to be associated with a subset of fetal bilateral hyperechogenic kidneys (3) and other kidney diseases diagnosed before birth (4). Besides diabetes, nonrenal anomalies involving Mullerian and Wolffian derivatives, liver and pancreas abnormalities, hyperuricemia with or without gout (5), and hypomagnesemia (6) have been reported.…”

HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting

“…5,6 Hnf1b deletion in mouse collecting ducts causes cysts. 7,8 Furthermore, Hnf1b upregulates transcription of uromodulin (Umod), polycystic kidney and hepatic disease 1 (Pkhd1), and polycystic kidney disease (Pkd2), the human homologues of which are respectively mutated in medullary cystic kidney disease type 2, autosomal recessive polycystic kidney disease (PKD), and a subset of autosomal dominant PKD.…”