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Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling |
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| Authors: | Li Yun Laue Kathrin Temtamy Samia Aglan Mona Kotan L Damla Yigit Gökhan Canan Husniye Pawlik Barbara Nürnberg Gudrun Wakeling Emma L Quarrell Oliver W Baessmann Ingelore Lanktree Matthew B Yilmaz Mustafa Hegele Robert A Amr Khalda May Klaus W Nürnberg Peter Topaloglu A Kemal Hammerschmidt Matthias Wollnik Bernd |
| Institution: | 1 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 2 Institute of Human Genetics, University Hospital Cologne, University of Cologne, Cologne, Germany 3 Institute of Developmental Biology, University of Cologne, Cologne, Germany 4 Departments of Clinical and Molecular Genetics, Division of Human Genetics and Human Genome Research, National Research Centre, Cairo, Egypt 5 Department of Biotechnology, Institute of Sciences, Cukurova University, Adana, Turkey 6 Department of Forensic Medicine, Faculty of Medicine, Cukurova University, Adana, Turkey 7 Cologne Center for Genomics, University of Cologne, Cologne, Germany 8 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany 9 North West Thames Regional Genetic Service, Harrow, London, UK 10 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK 11 Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada 12 Department of Pediatric Allergy and Immunology, Faculty of Medicine, Cukurova University, Adana, Turkey 13 Genomatix Software GmbH, München, Germany 14 Department of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Adana, Turkey |
| Abstract: | Altered Bone Morphogenetic Protein (BMP) signaling leads to multiple developmental defects, including brachydactyly and deafness. Here we identify chondroitin synthase 1 (CHSY1) as a potential mediator of BMP effects. We show that loss of human CHSY1 function causes autosomal-recessive Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by limb malformations, short stature, and hearing loss. After mapping the TPBS locus to chromosome 15q26-qterm, we identified causative mutations in five consanguineous TPBS families. In zebrafish, antisense-mediated chsy1 knockdown causes defects in multiple developmental processes, some of which are likely to also be causative in the etiology of TPBS. In the inner ears of zebrafish larvae, chsy1 is expressed similarly to the BMP inhibitor dan and in a complementary fashion to bmp2b. Furthermore, unrestricted Bmp2b signaling or loss of Dan activity leads to reduced chsy1 expression and, during epithelial morphogenesis, defects similar to those that occur upon Chsy1 inactivation, indicating that Bmp signaling affects inner-ear development by repressing chsy1. In addition, we obtained strikingly similar zebrafish phenotypes after chsy1 overexpression, which might explain why, in humans, brachydactyly can be caused by mutations leading either to loss or to gain of BMP signaling. |
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