Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans
| Autor: | Kai M. Schmidt-Ott, Amar J. Majmundar, Friedhelm Hildebrandt, Thomas M. Kitzler, Florian Buerger, Nina Mann, Maike Getwan, Sherif El Desoky, Michael M. Kaminski, Konstantin Deutsch, Tian Shen, Ana C. Onuchic-Whitford, Verena Klämbt, Jameela A. Kari, Youying Mao, Shirlee Shril, Soeren S. Lienkamp, Mohamed A. Shalaby, Max Werth, Jonathan Barasch |
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| Přispěvatelé: | University of Zurich |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition 10017 Institute of Anatomy 030232 urology & nephrology Kidney development 610 Medicine & health urologic and male genital diseases medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine Tubulopathy Exome Sequencing Animals Humans Medicine Child Exome sequencing Mice Knockout Transplantation Mutation Kidney business.industry medicine.disease Hypotonia Rats 3. Good health DNA-Binding Proteins Repressor Proteins HEK293 Cells 030104 developmental biology medicine.anatomical_structure Nephrology Cancer research 570 Life sciences biology Female Kidney Diseases ORIGINAL ARTICLES Single-Cell Analysis medicine.symptom business Transcription Factor Gene Transcription Factors Kidney disease |
| Zdroj: | Nephrol Dial Transplant |
| ISSN: | 1460-2385 0931-0509 |
| DOI: | 10.1093/ndt/gfaa215 |
| Popis: | Background An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis. Methods In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD. Results We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient’s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity. Conclusion Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy. |
| Databáze: | OpenAIRE |
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