Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development

Asaf Vivante, Marc Jens Kleppa, Julian Schulz, Stefan Kohl, Amita Sharma, Jing Chen, Shirlee Shril, Daw Yang Hwang, Anna Carina Weiss, Michael M. Kaminski, Rachel Shukrun, Markus J. Kemper, Anja Lehnhardt, Rolf Beetz, Simone Sanna-Cherchi, Miguel Verbitsky, Ali G. Gharavi, Helen M. Stuart, Sally A. Feather, Judith A. GoodshipTimothy H.J. Goodship, Adrian S. Woolf, Sjirk J. Westra, Daniel P. Doody, Stuart B. Bauer, Richard S. Lee, Rosalyn M. Adam, Weining Lu, Heiko M. Reutter, Elijah O. Kehinde, Erika J. Mancini, Richard P. Lifton, Velibor Tasic, Soeren S. Lienkamp, Harald Jüppner, Andreas Kispert, Friedhelm Hildebrandt

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.

Original languageEnglish
Article number1912
Pages (from-to)291-301
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - Aug 6 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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