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

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Item Type:	Article
Title:	Mutations in TBX18 cause dominant urinary tract malformations via transcriptional dysregulation of ureter development
Creators Name:	Vivante, Asaf, Kleppa, M.J., Schulz, J., Kohl, S., Sharma, A., Chen, J., Shril, S., Hwang, D.Y., Weiss, A.C., Kaminski, M.M., Shukrun, R., Kemper, M.J., Lehnhardt, A., Beetz, R., Sanna-Cherchi, S., Verbitsky, M., Gharavi, A.G., Stuart, H.M., Feather, S.A., Goodship, J.A., Goodship, T.H.J., Woolf, A.S., Westra, S.J., Doody, D.P., Bauer, S.B., Lee, R.S., Adam, R.M., Lu, W., Reutter, H.M., Kehinde, E.O., Mancini, E.J., Lifton, R.P., Tasic, V., Lienkamp, S.S., Jüppner, H., 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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