Article ; Online: Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model.
2021 Volume 14, Issue 5
Abstract: Heterozygous mutations in HNF1B cause the complex syndrome renal cysts and diabetes (RCAD), characterized by developmental abnormalities of the kidneys, genital tracts and pancreas, and a variety of renal, pancreas and liver dysfunctions. The ... ...
| Abstract | Heterozygous mutations in HNF1B cause the complex syndrome renal cysts and diabetes (RCAD), characterized by developmental abnormalities of the kidneys, genital tracts and pancreas, and a variety of renal, pancreas and liver dysfunctions. The pathogenesis underlying this syndrome remains unclear as mice with heterozygous null mutations have no phenotype, while constitutive/conditional Hnf1b ablation leads to more severe phenotypes. We generated a novel mouse model carrying an identified human mutation at the intron-2 splice donor site. Unlike heterozygous mice previously characterized, mice heterozygous for the splicing mutation exhibited decreased HNF1B protein levels and bilateral renal cysts from embryonic day 15, originated from glomeruli, early proximal tubules (PTs) and intermediate nephron segments, concurrently with delayed PT differentiation, hydronephrosis and rare genital tract anomalies. Consistently, mRNA sequencing showed that most downregulated genes in embryonic kidneys were primarily expressed in early PTs and the loop of Henle and involved in ion/drug transport, organic acid and lipid metabolic processes, while the expression of previously identified targets upon Hnf1b ablation, including cystic disease genes, was weakly or not affected. Postnatal analyses revealed renal abnormalities, ranging from glomerular cysts to hydronephrosis and, rarely, multicystic dysplasia. Urinary proteomics uncovered a particular profile predictive of progressive decline in kidney function and fibrosis, and displayed common features with a recently reported urine proteome in an RCAD pediatric cohort. Altogether, our results show that reduced HNF1B levels lead to developmental disease phenotypes associated with the deregulation of a subset of HNF1B targets. They further suggest that this model represents a unique clinical/pathological viable model of the RCAD disease. |
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| MeSH term(s) | Animals ; Animals, Newborn ; Cell Polarity ; Central Nervous System Diseases/genetics ; Central Nervous System Diseases/pathology ; Cilia/pathology ; Dental Enamel/abnormalities ; Dental Enamel/pathology ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/pathology ; Disease Models, Animal ; Embryo, Mammalian/pathology ; Gene Dosage ; Gene Expression Profiling ; Genes, Developmental ; Haploinsufficiency/genetics ; Hepatocyte Nuclear Factor 1-beta/genetics ; Heterozygote ; Humans ; Hydronephrosis/complications ; Kidney Diseases, Cystic/genetics ; Kidney Diseases, Cystic/pathology ; Kidney Glomerulus/pathology ; Kidney Tubules/pathology ; Mice, Inbred C57BL ; Mutation/genetics ; Nephrons/pathology ; RNA Splicing/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Severity of Illness Index ; Mice |
| Chemical Substances | HNF1B protein, human ; Hnf1b protein, mouse ; RNA, Messenger ; Hepatocyte Nuclear Factor 1-beta (138674-15-4) |
| Language | English |
| Publishing date | 2021-05-04 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2451104-3 |
| ISSN | 1754-8411 ; 1754-8403 |
| ISSN (online) | 1754-8411 |
| ISSN | 1754-8403 |
| DOI | 10.1242/dmm.047498 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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