Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans
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Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans. / Klämbt, Verena; Werth, Max; Onuchic-Whitford, Ana C; Getwan, Maike; Kitzler, Thomas M; Buerger, Florian; Mao, Youying; Deutsch, Konstantin; Mann, Nina; Majmundar, Amar J; Kaminski, Michael M; Shen, Tian; Schmidt-Ott, Kai M; Shalaby, Mohamed; El Desoky, Sherif; Kari, Jameela A; Shril, Shirlee; Lienkamp, Soeren S; Barasch, Jonathan; Hildebrandt, Friedhelm.
in: NEPHROL DIAL TRANSPL, Jahrgang 36, Nr. 2, 25.01.2021, S. 237-246.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans
AU - Klämbt, Verena
AU - Werth, Max
AU - Onuchic-Whitford, Ana C
AU - Getwan, Maike
AU - Kitzler, Thomas M
AU - Buerger, Florian
AU - Mao, Youying
AU - Deutsch, Konstantin
AU - Mann, Nina
AU - Majmundar, Amar J
AU - Kaminski, Michael M
AU - Shen, Tian
AU - Schmidt-Ott, Kai M
AU - Shalaby, Mohamed
AU - El Desoky, Sherif
AU - Kari, Jameela A
AU - Shril, Shirlee
AU - Lienkamp, Soeren S
AU - Barasch, Jonathan
AU - Hildebrandt, Friedhelm
N1 - © The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
PY - 2021/1/25
Y1 - 2021/1/25
N2 - 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.
AB - 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.
KW - Animals
KW - Child
KW - DNA-Binding Proteins/genetics
KW - Epithelial-Mesenchymal Transition
KW - Female
KW - HEK293 Cells
KW - Humans
KW - Kidney Diseases/etiology
KW - Mice
KW - Mice, Knockout
KW - Mutation
KW - Rats
KW - Repressor Proteins/genetics
KW - Single-Cell Analysis
KW - Transcription Factors/genetics
KW - Exome Sequencing
U2 - 10.1093/ndt/gfaa215
DO - 10.1093/ndt/gfaa215
M3 - SCORING: Journal article
C2 - 33097957
VL - 36
SP - 237
EP - 246
JO - NEPHROL DIAL TRANSPL
JF - NEPHROL DIAL TRANSPL
SN - 0931-0509
IS - 2
ER -