Mutations in the TGFβ Binding-Protein-Like Domain 5 of FBN1 Are Responsible for Acromicric and Geleophysic Dysplasias
Year: 2011
Type: article
Study design: Observational Study
Abstract: Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFβ signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.
Authors: Carine Le Goff, Clémentine Mahaut, Lauren W. Wang, Slimane Allali, Avinash Abhyankar, Sacha Jensen, Louise Zylberberg, Gwenaelle Collod-Beroud, Damien Bonnet, Yasemin Alanay, Angela F. Brady, Marie-Pierre Cordier, Koen Devriendt, David Genevieve, Pelin Özlem Simsek Kiper, Hiroshi Kitoh, Deborah Krakow, Sally Ann Lynch, Martine Le Merrer, André Mégarbane, Geert Mortier, Sylvie Odent, Michel Polak, Marianne Rohrbach, David Sillence, Irene Stolte-Dijkstra, Andrea Superti-Furga, David L. Rimoin, Vicken Topouchian, Sheila Unger, Bernhard Zabel, Christine Bole-Feysot, Patrick Nitschke, Penny Handford, Jean-Laurent Casanova, Catherine Boileau, Suneel S. Apte, Arnold Munnich, Valérie Cormier-Daire
Institutions: Hôpital Necker-Enfants Malades, Inserm, Institut Necker Enfants Malades, Université Paris Descartes, Cleveland Clinic, Cleveland Clinic Research, Rockefeller University, University of Oxford, Centre National de la Recherche Scientifique, Université Pierre-et-Marie-Curie, Université de Montpellier, Université Montpellier 1, Hacettepe University, Northwick Park Hospital, Hôpital Femme Mère Enfant, KU Leuven, Nagoya University, University of California, Los Angeles, Children's Health Ireland at Crumlin, Saint Joseph University, University of Antwerp, Antwerp University Hospital, Institut de génétique et de développement de Rennes, Université Rennes 1, Université de Rennes, Assistance Publique – Hôpitaux de Paris, University Children's Hospital Zurich, Children's Hospital at Westmead, University Medical Center Groningen, University of Groningen, University of Lausanne, Cedars-Sinai Medical Center, University of Freiburg, University Medical Center Freiburg, Human Genetic of Infectious Diseases, Hôpital Ambroise-Paré, Hôpital Bichat-Claude-Bernard, Université Paris Diderot
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,150
OpenAlex ID: W2033610825