title: Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development.
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.
authors.affiliation: 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.
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover 30625, Germany.
authors.forename: Marc-Jens
authors.initials: MJ
authors.lastname: Kleppa
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Schulz
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Pediatric Nephrology Unit and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shirlee
authors.initials: S
authors.lastname: Shril
authors.affiliation: 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.
authors.forename: Daw-Yang
authors.initials: DY
authors.lastname: Hwang
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover 30625, Germany.
authors.forename: Anna-Carina
authors.initials: AC
authors.lastname: Weiss
authors.affiliation: Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kaminski
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Shukrun
authors.affiliation: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
authors.affiliation: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Lehnhardt
authors.affiliation: Center for Pediatric and Adolescent Medicine, University Medical Clinic, 55131 Mainz, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Beetz
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10023, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Sanna-Cherchi
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10023, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Verbitsky
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10023, USA.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.affiliation: 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.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Stuart
authors.affiliation: Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Feather
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
authors.affiliation: 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.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.affiliation: Pediatric Radiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sjirk J
authors.initials: SJ
authors.lastname: Westra
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Doody
authors.affiliation: Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Bauer
authors.affiliation: Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Lee
authors.affiliation: Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.affiliation: Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA.
authors.forename: Weining
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Neonatology, Children's Hospital, University of Bonn, 53127 Bonn, Germany.
authors.forename: Heiko M
authors.initials: HM
authors.lastname: Reutter
authors.affiliation: Division of Urology, Department of Surgery, Kuwait University, 13110 Safat, Kuwait.
authors.forename: Elijah O
authors.initials: EO
authors.lastname: Kehinde
authors.affiliation: 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.
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Mancini
authors.affiliation: Department of Human Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Medical School Skopje, University Children's Hospital, 1000 Skopje, Macedonia.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), 79104 Freiburg, Germany.
authors.forename: Soeren S
authors.initials: SS
authors.lastname: Lienkamp
authors.affiliation: Pediatric Nephrology Unit and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover 30625, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.affiliation: 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.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D001483:Base Sequence; D024202:Electrophoretic Mobility Shift Assay; D059472:Exome / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000196:embryology*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D020825:T-Box Domain Proteins / Q000235:genetics*; D014513:Ureter / Q000196:embryology*; D014551:Urinary Tract / Q000002:abnormalities*
chemical_list: D020825:T-Box Domain Proteins; C523796:Tbx18 protein, human