Mutations in TBX18 cause dominant urinary tract malformations via transcriptional dysregulation of ureter development

Item Type:	Article
Title:	Mutations in TBX18 cause dominant urinary tract malformations via transcriptional dysregulation of ureter development
Creators Name:	Vivante, Asaf and Kleppa, M.J. and Schulz, J. and Kohl, S. and Sharma, A. and Chen, J. and Shril, S. and Hwang, D.Y. and Weiss, A.C. and Kaminski, M.M. and Shukrun, R. and Kemper, M.J. and Lehnhardt, A. and Beetz, R. and Sanna-Cherchi, S. and Verbitsky, M. and Gharavi, A.G. and Stuart, H.M. and Feather, S.A. and Goodship, J.A. and Goodship, T.H.J. and Woolf, A.S. and Westra, S.J. and Doody, D.P. and Bauer, S.B. and Lee, R.S. and Adam, R.M. and Lu, W. and Reutter, H.M. and Kehinde, E.O. and Mancini, E.J. and Lifton, R.P. and Tasic, V. and Lienkamp, S.S. and Jüppner, H. and Kispert, A. and Hildebrandt, F.
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.
Keywords:	Base Sequence, Developmental Gene Expression Regulation, DNA Sequence Analysis, Dominant Genes, Electrophoretic Mobility Shift Assay, Exome, Fluorescence Microscopy, HEK293 Cells, Immunohistochemistry, Immunoprecipitation, Molecular Sequence Data, Mutation, Pedigree, Smooth Muscle, T-Box Domain Proteins, Ureter, Urinary Tract
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	97
Number:	2
Page Range:	291-301
Date:	6 August 2015
Official Publication:	https://doi.org/10.1016/j.ajhg.2015.07.001
PubMed:	View item in PubMed

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