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

Lookup NU author(s): Professor Judith Goodship, Professor Tim Goodship

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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.


Publication metadata

Author(s): Vivante A, Kleppa MJ, Schulz J, Kohl S, Sharma A, Chen J, Shril S, Hwang DY, Weiss AC, Kaminski MM, Shukrun R, Kemper MJ, Lehnhardt A, Beetz R, Sanna-Cherchi S, Verbitsky M, Gharavi AG, Stuart HM, Feather SA, Goodship JA, Goodship THJ, Woolf AS, Westra SJ, Doody DP, Bauer SB, Lee RS, Adam RM, Lu W, Reutter HM, Kehinde EO, Mancini EJ, Lifton RP, Tasic V, Lienkamp SS, Juppner H, Kispert A, Hildebrandt F

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2015

Volume: 97

Issue: 2

Pages: 291-301

Print publication date: 06/08/2015

Online publication date: 30/07/2015

Acceptance date: 07/07/2015

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ajhg.2015.07.001

DOI: 10.1016/j.ajhg.2015.07.001


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Funding

Funder referenceFunder name
Kidney Research UK
Boston Children's Hospital
Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy) at Hannover Medical School
Emmy Noether programme
Fulbright postdoctoral scholar award
March of Dimes
NIHR UK
066647Wellcome Trust
5U54HG006504NIH
DK 46718NIH
DK078226NIH
DK088767NIH
DK096238NIH
G0600040Medical Research Council
Ki72817-1
MR/L002744/1Medical Research Council
SFB1140German Research Foundation (DFG)

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