Verena Klämbt1, Max Werth2, Ana C Onuchic-Whitford1,3, Maike Getwan4, Thomas M Kitzler1, Florian Buerger1, Youying Mao1, Konstantin Deutsch1, Nina Mann1, Amar J Majmundar1, Michael M Kaminski5,6, Tian Shen2, Kai M Schmidt-Ott6, Mohamed Shalaby7, Sherif El Desoky7, Jameela A Kari7, Shirlee Shril1, Soeren S Lienkamp4,8, Jonathan Barasch2, Friedhelm Hildebrandt1. 1. Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. 2. Division of Nephrology, Columbia University, New York, NY, USA. 3. Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 4. Department of Medicine, Renal Division, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 5. Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. 6. Department of Nephrology and Medical Intensive Care, Charité - Universitaetsmedizin Berlin, Germany. 7. Pediatric Nephrology Center of Excellence and Pediatric Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. 8. Institute of Anatomy, University of Zurich, Zurich, Switzerland.
Abstract
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.
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.
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Authors: Nathan R Hill; Samuel T Fatoba; Jason L Oke; Jennifer A Hirst; Christopher A O'Callaghan; Daniel S Lasserson; F D Richard Hobbs Journal: PLoS One Date: 2016-07-06 Impact factor: 3.240
Authors: Friedhelm Hildebrandt; Saskia F Heeringa; Franz Rüschendorf; Massimo Attanasio; Gudrun Nürnberg; Christian Becker; Dominik Seelow; Norbert Huebner; Gil Chernin; Christopher N Vlangos; Weibin Zhou; John F O'Toole; Bethan E Hoskins; Matthias T F Wolf; Bernward G Hinkes; Hassan Chaib; Shazia Ashraf; Dominik S Schoeb; Bugsu Ovunc; Susan J Allen; Virginia Vega-Warner; Eric Wise; Heather M Harville; Robert H Lyons; Joseph Washburn; James Macdonald; Peter Nürnberg; Edgar A Otto Journal: PLoS Genet Date: 2009-01-23 Impact factor: 5.917