1. Am J Hum Genet. 2022 May 5;109(5):928-943. doi: 10.1016/j.ajhg.2022.03.015. Epub 2022 Apr 8. Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations. Devane J(1), Ott E(1), Olinger EG(2), Epting D(1), Decker E(3), Friedrich A(3), Bachmann N(3), Renschler G(3), Eisenberger T(3), Briem-Richter A(4), Grabhorn EF(4), Powell L(2), Wilson IJ(5), Rice SJ(5), Miles CG(2), Wood K(6); Genomics England Research Consortium; Trivedi P(7), Hirschfield G(8), Pietrobattista A(9), Wohler E(10), Mezina A(11), Sobreira N(10), Agolini E(12), Maggiore G(9), Dahmer-Heath M(13), Yilmaz A(14), Boerries M(15), Metzger P(16), Schell C(17), Grünewald I(18), Konrad M(13), König J(13), Schlevogt B(19), Sayer JA(20), Bergmann C(21). Author information: (1)Department of Medicine IV, Faculty of Medicine, Medical Center-University of Freiburg, 79106 Freiburg, Germany. (2)Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. (3)Medizinische Genetik Mainz, Limbach Genetics, 55128 Mainz, Germany. (4)University Medical Center Hamburg-Eppendorf, Department of Pediatrics, 20251 Hamburg, Germany. (5)Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. (6)Histopathology Department, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK. (7)NIHR Birmingham BRC, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham B15 2TT, UK; Liver Unit, University Hospitals Birmingham, Birmingham B15 2GW, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; Institute of Applied Health Research, University of Birmingham, Birmingham B15 2TT, UK. (8)Toronto Centre for Liver Disease, University Health Network, Toronto, ON M6H 3M1, Canada. (9)Hepatogastroenterology and Liver Transplant Unit and Medical Genetics Laboratory, IRCCS Bambino Gesù Children's Hospital, 00165 Rome, Italy. (10)McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. (11)Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (12)Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy. (13)Department of General Pediatrics, University Hospital Münster, 48149 Münster, Germany. (14)Department of Cardiology I, University Hospital Münster, 48149 Münster, Germany. (15)Institute of Medical Bioinformatics and Systems Medicine Medical Center - University of Freiburg, Medical Faculty, University of Freiburg, 79110 Freiburg, Germany; The German Cancer Consortium, Partner Site Freiburg and Cancer Research Center, 69120 Heidelberg, Germany. (16)Institute of Medical Bioinformatics and Systems Medicine Medical Center - University of Freiburg, Medical Faculty, University of Freiburg, 79110 Freiburg, Germany. (17)Institute for Pathology, Medical Center - University of Freiburg, Medical Faculty, University of Freiburg, 79002 Freiburg, Germany. (18)Institute for Pathology, University Hospital Münster, 48149 Münster, Germany. (19)Department of Internal Medicine B, Gastroenterology, University Hospital Münster, 48149 Münster, Germany. (20)Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Renal Services, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK; Newcastle Biomedical Research Centre, NIHR, Newcastle upon Tyne NE4 5PL, UK. Electronic address: john.sayer@newcastle.ac.uk. (21)Department of Medicine IV, Faculty of Medicine, Medical Center-University of Freiburg, 79106 Freiburg, Germany; Medizinische Genetik Mainz, Limbach Genetics, 55128 Mainz, Germany. Electronic address: carsten.bergmann@medgen-mainz.de. Organ fibrosis is a shared endpoint of many diseases, yet underlying mechanisms are not well understood. Several pathways governed by the primary cilium, a sensory antenna present on most vertebrate cells, have been linked with fibrosis. Ciliopathies usually start early in life and represent a considerable disease burden. We performed massively parallel sequencing by using cohorts of genetically unsolved individuals with unexplained liver and kidney failure and correlated this with clinical, imaging, and histopathological analyses. Mechanistic studies were conducted with a vertebrate model and primary cells. We detected bi-allelic deleterious variants in TULP3, encoding a critical adaptor protein for ciliary trafficking, in a total of 15 mostly adult individuals, originating from eight unrelated families, with progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy with atypical fibrotic patterns on histopathology. We recapitulated the human phenotype in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals. Further, we show interaction between TULP3 and the nuclear deacetylase SIRT1, with roles in DNA damage repair and fibrosis, and report increased DNA damage ex vivo. Transcriptomic studies demonstrated upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy and WNT and TGF-β signaling. These findings identify variants in TULP3 as a monogenic cause for progressive degenerative disease of major organs in which affected individuals benefit from early detection and improved clinical management. Elucidation of mechanisms crucial for DNA damage repair and tissue maintenance will guide novel therapeutic avenues for this and similar genetic and non-genomic diseases. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.ajhg.2022.03.015 PMCID: PMC9118107 PMID: 35397207 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests E.D., A.F., N.B., G.R., and T.E. are employees of Medizinische Genetik Mainz. C.B. is an employee and managing director of Medizinische Genetik Mainz and Limbach Genetics GmbH. All other authors declare no competing interests.