Faulty Initiation of Proteoglycan Synthesis Causes Cardiac and Joint Defects |
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| Authors: | Sevjidmaa Baasanjav Lihadh Al-Gazali Taishi Hashiguchi Shuji Mizumoto Bjoern Fischer Denise Horn Dominik Seelow Bassam R Ali Samir AA Aziz Ruth Langer Ahmed AH Saleh Christian Becker Gudrun Nürnberg Vincent Cantagrel Joseph G Gleeson Delphine Gomez Jean-Baptiste Michel Sigmar Stricker Tom H Lindner Peter Nürnberg Kazuyuki Sugahara Stefan Mundlos Katrin Hoffmann |
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| Institution: | 1Institute of Medical Genetics, Charité University Medicine, Augustenburger Platz 1, 13353 Berlin, Germany;2Division of Nephrology, Department of Internal Medicine, University Clinic Leipzig, Liebigstr. 20, 04103 Leipzig, Germany;3Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates;4Laboratory of Proteoglycan Signaling and Therapeutics, Faculty of Advanced Life Science, Graduate School of Life Science, Hokkaido University, Frontier Research Center for Post-Genomic Science and Technology, West-11, North-21, Kita-ku, Sapporo 001-0021, Japan;5Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates;6Department of Pediatrics, Saqr Hospital, P.O. Box 5450, Ras Al Khaimah, United Arab Emirates;7Department of Radiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates;8Cologne Center for Genomics (CCG), University of Cologne, Weyertal 115b, 50931 Köln, Germany;9Neurogenetics Laboratory, Department of Neurosciences, University of California, San Diego, Leichtag 3A16, 9500 Gilman Drive, La Jolla, CA 92093, USA;10INSERM Unit 698, Cardiovascular remodeling, 46, rue Henri Huchard, 75018 Paris, France;11Max Planck Institute for Molecular Genetics, Development and Disease, Ihnestraße 63-73, 14195 Berlin, Germany;12The Berlin Aging Study II, Research Group on Geriatrics, Charité University Medicine, Reinickendorfer Str. 61, 13347 Berlin, Germany;13Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany |
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| Abstract: | Proteoglycans are a major component of extracellular matrix and contribute to normal embryonic and postnatal development by ensuring tissue stability and signaling functions. We studied five patients with recessive joint dislocations and congenital heart defects, including bicuspid aortic valve (BAV) and aortic root dilatation. We identified linkage to chromosome 11 and detected a mutation (c.830G>A, p.Arg277Gln) in B3GAT3, the gene coding for glucuronosyltransferase-I (GlcAT-I). The enzyme catalyzes an initial step in the synthesis of glycosaminoglycan side chains of proteoglycans. Patients'' cells as well as recombinant mutant protein showed reduced glucuronyltransferase activity. Patient fibroblasts demonstrated decreased levels of dermatan sulfate, chondroitin sulfate, and heparan sulfate proteoglycans, indicating that the defect in linker synthesis affected all three lines of O-glycanated proteoglycans. Further studies demonstrated that GlcAT-I resides in the cis and cis-medial Golgi apparatus and is expressed in the affected tissues, i.e., heart, aorta, and bone. The study shows that reduced GlcAT-I activity impairs skeletal as well as heart development and results in variable combinations of heart malformations, including mitral valve prolapse, ventricular septal defect, and bicuspid aortic valve. The described family constitutes a syndrome characterized by heart defects and joint dislocations resulting from altered initiation of proteoglycan synthesis (Larsen-like syndrome, B3GAT3 type). |
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