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Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia |
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| Authors: | Bergmann Carsten Fliegauf Manfred Brüchle Nadina Ortiz Frank Valeska Olbrich Heike Kirschner Jan Schermer Bernhard Schmedding Ingolf Kispert Andreas Kränzlin Bettina Nürnberg Gudrun Becker Christian Grimm Tiemo Girschick Gundula Lynch Sally A Kelehan Peter Senderek Jan Neuhaus Thomas J Stallmach Thomas Zentgraf Hanswalter Nürnberg Peter Gretz Norbert Lo Cecilia Lienkamp Soeren Schäfer Tobias Walz Gerd Benzing Thomas Zerres Klaus Omran Heymut |
| Institution: | 1 Department of Human Genetics, RWTH Aachen University, 52074 Aachen, Germany 2 Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany 3 Department of Medicine IV and Kidney Research Center Cologne, University of Cologne, 50924 Cologne, Germany 4 Institute for Molecular Biology, Medizinische Hochschule Hannover, 30625 Hannover, Germany 5 Medical Research Center, Klinikum Mannheim, University of Heidelberg, 68167 Mannheim, Germany 6 Cologne Center for Genomics, University of Cologne, 50674 Cologne, Germany 7 RZPD Deutsches Ressourcenzentrum für Genomforschung GmbH, 13125 Berlin, Germany 8 Department of Human Genetics, University of Würzburg, 97074 Würzburg, Germany 9 Department of Obstetrics and Gynecology, University of Würzburg, 97080 Würzburg, Germany 10 National Centre for Medical Genetics, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland 11 Department of Histopathology, National Maternity Hospital, Dublin 2, Ireland 12 Nephrology Unit, University Children's Hospital Zürich, 8032 Zürich, Switzerland 13 Department of Pathology, University Zürich, 8091 Zürich, Switzerland 14 Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany 15 Institute for Genetics, University of Cologne, 50674 Cologne, Germany 16 Laboratory of Developmental Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1583, USA 17 Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany |
| Abstract: | Many genetic diseases have been linked to the dysfunction of primary cilia, which occur nearly ubiquitously in the body and act as solitary cellular mechanosensory organelles. The list of clinical manifestations and affected tissues in cilia-related disorders (ciliopathies) such as nephronophthisis is broad and has been attributed to the wide expression pattern of ciliary proteins. However, little is known about the molecular mechanisms leading to this dramatic diversity of phenotypes. We recently reported hypomorphic NPHP3 mutations in children and young adults with isolated nephronophthisis and associated hepatic fibrosis or tapetoretinal degeneration. Here, we chose a combinatorial approach in mice and humans to define the phenotypic spectrum of NPHP3/Nphp3 mutations and the role of the nephrocystin-3 protein. We demonstrate that the pcy mutation generates a hypomorphic Nphp3 allele that is responsible for the cystic kidney disease phenotype, whereas complete loss of Nphp3 function results in situs inversus, congenital heart defects, and embryonic lethality in mice. In humans, we show that NPHP3 mutations can cause a broad clinical spectrum of early embryonic patterning defects comprising situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulas, and a wide range of congenital anomalies of the kidney and urinary tract (CAKUT). On the functional level, we show that nephrocystin-3 directly interacts with inversin and can inhibit like inversin canonical Wnt signaling, whereas nephrocystin-3 deficiency leads in Xenopus laevis to typical planar cell polarity defects, suggesting a role in the control of canonical and noncanonical (planar cell polarity) Wnt signaling. |
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