ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on X

Kidney Week

Abstract: FR-OR076

TFCP2L1 Mutations Cause a Novel Distal Tubulopathy in Humans

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Klambt, Verena, Boston Children"s Hospital, Boston, Massachusetts, United States
  • Werth, Max, Columbia University, New York, New York, United States
  • Kaminski, Michael, University Hospital Freiburg, Freiburg, BW, Germany
  • Lienkamp, Soeren S., University Hospital Freiburg, Freiburg, BW, Germany
  • Schmidt-Ott, Kai M., Charite - Universitaetsmedizin Berlin, Max-Delbrueck Center for Molecular Medicine, Berlin, Germany
  • Roske, Yvette, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
  • Wang, Jianhui, Max Delbrück Center for Molecular Medicine, Berlin, Germany
  • Heinemann, Udo, Max Delbrück Center for Molecular Medicine, Berlin, Germany
  • Barasch, Jonathan M., Columbia Presbyterian, New York, New York, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in 20% of individuals. To date, >250 monogenic causative genes have been identified for the most common etiologies of CKD evident before age 25 years suggesting mechanisms of renal pathogenesis.


We performed whole exome sequencing to identify novel monogenic causes of CKD in ~1,000 families with renal tubulopathy/ echogenic kidneys.


We discovered 2 different recessive, homozygous mutations in TFCP2L1 (Transcription Factor CP2 Like 1) in 2 consanguineous families with CKD. Family B2003 with CKD at the age of 2 years, episodes of severe hypochloremic, hypokalemic alkalosis, cataracts, seizures, developmental delay, and hypotonia encoded a homozygous Ser290Phefs*5 mutation. A second child encoded a homozygous Gln168Arg mutation in A5048 with onset of CKD by 2 years of age, loss of urinary potassium and chloride, hypotonia and deafness. The variants are disease causing by SIFT, MutTaster and PolyPhen2 prediction programs and are absent from gnomAD database. Gln168Arg is located in the DNA-binding domain positioned at the start of the L10 loop pointing into the DNA minor groove. Tfcp2l1 is a transcription factor expressed in the thick limb of Henle, distal convoluted tubule, connecting segments and especially in the intercalating cells (ICs) in collecting ducts. Tfcp2l1 alone is sufficient to induce tubulogenesis in rat progenitors and is required for normal maturation of the distal nephron and collecting ducts in mice (Yamaguchi, Development, 2006; Werth, Elife, 2017). Tfcp2l1 knockout mice display loss of expression of direct binding targets of Tfcp2l1 including ion transporters in different segments of the distal nephron and regulatory proteins determining cell identity. A knockout caused renal hypoplasia, polyuria, renal potassium and chloride loss (Yamaguchi, Development 133:4737, 2006) and disruption of collecting duct patterning characterized by the deletion of ICs (Werth, eLIFE, 2017). Consistently, in Xenopus larvae skin tfcp2l1 localizes to foxi1+ ICs.


We here identified TFCP2L1 mutations as a potential novel cause of distal tubulopathy in humans. Modeling these mutations in mice and segment specific deletions will reveal the full functions of Tfcp2l1.