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Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development.
Vivante, Asaf; Kleppa, Marc-Jens; Schulz, Julian; Kohl, Stefan; Sharma, Amita; Chen, Jing; Shril, Shirlee; Hwang, Daw-Yang; Weiss, Anna-Carina; Kaminski, Michael M; Shukrun, Rachel; Kemper, Markus J; Lehnhardt, Anja; Beetz, Rolf; Sanna-Cherchi, Simone; Verbitsky, Miguel; Gharavi, Ali G; Stuart, Helen M; Feather, Sally A; Goodship, Judith A; Goodship, Timothy H J; Woolf, Adrian S; Westra, Sjirk J; Doody, Daniel P; Bauer, Stuart B; Lee, Richard S; Adam, Rosalyn M; Lu, Weining; Reutter, Heiko M; Kehinde, Elijah O; Mancini, Erika J; Lifton, Richard P; Tasic, Velibor; Lienkamp, Soeren S; Jüppner, Harald; Kispert, Andreas; Hildebrandt, Friedhelm.
Afiliación
  • Vivante A; 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.
  • Kleppa MJ; Institut für Molekularbiologie, Medizinische Hochschule Hannover 30625, Germany.
  • Schulz J; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Kohl S; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Sharma A; Pediatric Nephrology Unit and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Chen J; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Shril S; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Hwang DY; 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.
  • Weiss AC; Institut für Molekularbiologie, Medizinische Hochschule Hannover 30625, Germany.
  • Kaminski MM; Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany.
  • Shukrun R; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Kemper MJ; Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Lehnhardt A; Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Beetz R; Center for Pediatric and Adolescent Medicine, University Medical Clinic, 55131 Mainz, Germany.
  • Sanna-Cherchi S; Department of Medicine, Columbia University, New York, NY 10023, USA.
  • Verbitsky M; Department of Medicine, Columbia University, New York, NY 10023, USA.
  • Gharavi AG; Department of Medicine, Columbia University, New York, NY 10023, USA.
  • Stuart HM; 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.
  • Feather SA; Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK.
  • Goodship JA; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • Goodship TH; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • Woolf AS; 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.
  • Westra SJ; Pediatric Radiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Doody DP; Department of Pediatric Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Bauer SB; Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Lee RS; Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Adam RM; Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Lu W; Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA.
  • Reutter HM; Department of Neonatology, Children's Hospital, University of Bonn, 53127 Bonn, Germany.
  • Kehinde EO; Division of Urology, Department of Surgery, Kuwait University, 13110 Safat, Kuwait.
  • Mancini EJ; 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.
  • Lifton RP; Department of Human Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute.
  • Tasic V; Medical School Skopje, University Children's Hospital, 1000 Skopje, Macedonia.
  • Lienkamp SS; Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), 79104 Freiburg, Germany.
  • Jüppner H; Pediatric Nephrology Unit and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Kispert A; Institut für Molekularbiologie, Medizinische Hochschule Hannover 30625, Germany.
  • Hildebrandt F; 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.
Am J Hum Genet ; 97(2): 291-301, 2015 Aug 06.
Article en En | MEDLINE | ID: mdl-26235987
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Uréter / Sistema Urinario / Regulación del Desarrollo de la Expresión Génica / Proteínas de Dominio T Box / Genes Dominantes / Músculo Liso / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2015 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Uréter / Sistema Urinario / Regulación del Desarrollo de la Expresión Génica / Proteínas de Dominio T Box / Genes Dominantes / Músculo Liso / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2015 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos