Identification of CANT1 Mutations in Desbuquois Dysplasia |
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Authors: | Cé line Huber,Bé né dicte Oulè s,Marta Bertoli,Mé lanie Fradin,Lihadh I. Al-Gazali,Pierre Bitoun,Alexander Krebs,Geert Mortier,Andrea Superti-Furga,Carine Le Goff,Patrizia Paterlini-Bré chot,Valé rie Cormier-Daire |
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Affiliation: | 1 Paris Descartes University, Department of Genetics and INSERM U781 and U807, Hôpital Necker Enfants Malades, 75015 Paris, France 2 The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy 3 Genetics Unit, Department of Pediatrics, Hacettepe University Faculty of Medicine, 06100 Sihhiyye, Ankara, Turkey 4 Department of Paediatrics, Faculty of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al-Ain, United Arab Emirates 5 Department of Medical Genetics, University Medical Center Utrecht, KC 04.084.2, PO Box 85090, 3508 AB Utrecht, The Netherlands 6 Hôpital Jean Verdier, 93140 Bondy, France 7 Perinatal Genetic Program, Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, 13084-971 Campinas, Seo Paulo, Brazil 8 Division of Pediatric Orthopedics, Orthopedic Hospital Speising, A-1130 Vienna, Austria 9 Center for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium 10 Stem Cell Research and Medical Genetic Department, Sarem Women Hospital, 13969 Teheran, Iran 11 Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, Mathildenstrasse 1, D-79106 Freiburg, Germany 12 Department of Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, 9054 Dunedin, New Zealand 13 Department of Pathology, Campus Bio-Medico University, Via Alvaro del Portillo 200, 00128 Rome, Italy |
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Abstract: | Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5′ UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process. |
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