Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans

TY - JOUR

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 -