Related resources
Full-text held externally
- PMID: 26235987
- UKPMCID: 26235987
- DOI: 10.1016/j.ajhg.2015.07.001
Search for item elsewhere
University researcher(s)
Academic department(s)
Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development.
Vivante, Asaf; Kleppa, Marc-Jens; Schulz, Julian; Kohl, Stefan; Sharma, Amita; Chen, Jing; Shril, Shirlee; Hwang, Daw-Yang; Weiss, Anna-Carina; Kaminski, Michael M; Shukrun, Rachel; Kemper, Markus J; Lehnhardt, Anja; Beetz, Rolf; Sanna-Cherchi, Simone; Verbitsky, Miguel; Gharavi, Ali G; Stuart, Helen M; Feather, Sally A; Goodship, Judith A; Goodship, Timothy H J; Woolf, Adrian S; Westra, Sjirk J; Doody, Daniel P; Bauer, Stuart B; Lee, Richard S; Adam, Rosalyn M; Lu, Weining; Reutter, Heiko M; Kehinde, Elijah O; Mancini, Erika J; Lifton, Richard P; Tasic, Velibor; Lienkamp, Soeren S; JĂĽppner, Harald; Kispert, Andreas; Hildebrandt, Friedhelm
American journal of human genetics. 2015;97(2):291-301.
Access to files
Full-text and supplementary files are not available from Manchester eScholar. Full-text is available externally using the following links:
Full-text held externally
- PMID: 26235987
- UKPMCID: 26235987
- DOI: 10.1016/j.ajhg.2015.07.001
Abstract
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.
Bibliographic metadata
- Vivante, Asaf
- Kleppa, Marc-Jens
- Schulz, Julian
- Kohl, Stefan
- Sharma, Amita
- Chen, Jing
- Shril, Shirlee
- Hwang, Daw-Yang
- Weiss, Anna-Carina
- Kaminski, Michael M
- Shukrun, Rachel
- Kemper, Markus J
- Lehnhardt, Anja
- Beetz, Rolf
- Sanna-Cherchi, Simone
- Verbitsky, Miguel
- Gharavi, Ali G
- Stuart, Helen M
- Feather, Sally A
- Goodship, Judith A
- Goodship, Timothy H J
- Woolf, Adrian S
- Westra, Sjirk J
- Doody, Daniel P
- Bauer, Stuart B
- Lee, Richard S
- Adam, Rosalyn M
- Lu, Weining
- Reutter, Heiko M
- Kehinde, Elijah O
- Mancini, Erika J
- Lifton, Richard P
- Tasic, Velibor
- Lienkamp, Soeren S
- JĂĽppner, Harald
- Kispert, Andreas
- Hildebrandt, Friedhelm
- 066647, Wellcome Trust, United Kingdom
- 5U54HG006504, NHGRI NIH HHS, United States
- DK078226, NIDDK NIH HHS, United States
- DK088767, NIDDK NIH HHS, United States
- DK096238, NIDDK NIH HHS, United States
- DK46718, NIDDK NIH HHS, United States
- G0600040, Medical Research Council, United Kingdom
- MR/L002744/1, Medical Research Council, United Kingdom
- , Department of Health, United Kingdom
- , Howard Hughes Medical Institute, United States