2. Academic Validation
  3. Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development

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

  • Am J Hum Genet. 2015 Aug 6;97(2):291-301. doi: 10.1016/j.ajhg.2015.07.001.
Asaf Vivante 1,  Marc-Jens Kleppa 2,  Julian Schulz 3,  Stefan Kohl 3,  Amita Sharma 4,  Jing Chen 3,  Shirlee Shril 3,  Daw-Yang Hwang 5,  Anna-Carina Weiss 2,  Michael M Kaminski 6,  Rachel Shukrun 3,  Markus J Kemper 7,  Anja Lehnhardt 7,  Rolf Beetz 8,  Simone Sanna-Cherchi 9,  Miguel Verbitsky 9,  Ali G Gharavi 9,  Helen M Stuart 10,  Sally A Feather 11,  Judith A Goodship 12,  Timothy H J Goodship 12,  Adrian S Woolf 10,  Sjirk J Westra 13,  Daniel P Doody 14,  Stuart B Bauer 15,  Richard S Lee 15,  Rosalyn M Adam 15,  Weining Lu 16,  Heiko M Reutter 17,  Elijah O Kehinde 18,  Erika J Mancini 19,  Richard P Lifton 20,  Velibor Tasic 21,  Soeren S Lienkamp 22,  Harald Jüppner 4,  Andreas Kispert 2,  Friedhelm Hildebrandt 23
Affiliations

Affiliations

  • 1 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer 52621, Israel.
  • 2 Institut für Molekularbiologie, Medizinische Hochschule Hannover 30625, Germany.
  • 3 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Pediatric Nephrology Unit and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 5 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 6 Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany.
  • 7 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 8 Center for Pediatric and Adolescent Medicine, University Medical Clinic, 55131 Mainz, Germany.
  • 9 Department of Medicine, Columbia University, New York, NY 10023, USA.
  • 10 Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester M13 9WL, UK.
  • 11 Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK.
  • 12 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • 13 Pediatric Radiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 14 Department of Pediatric Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 15 Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 16 Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA.
  • 17 Department of Neonatology, Children's Hospital, University of Bonn, 53127 Bonn, Germany.
  • 18 Division of Urology, Department of Surgery, Kuwait University, 13110 Safat, Kuwait.
  • 19 Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford OX3 7BN, UK; School of Life Sciences, University of Sussex, Brighton BN1 9QD, UK.
  • 20 Department of Human Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute.
  • 21 Medical School Skopje, University Children's Hospital, 1000 Skopje, Macedonia.
  • 22 Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), 79104 Freiburg, Germany.
  • 23 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
PMID: 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.

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