Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP |
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Authors: | Vissers Lisenka E L M Lausch Ekkehart Unger Sheila Campos-Xavier Ana Belinda Gilissen Christian Rossi Antonio Del Rosario Marisol Venselaar Hanka Knoll Ute Nampoothiri Sheela Nair Mohandas Spranger Jürgen Brunner Han G Bonafé Luisa Veltman Joris A Zabel Bernhard Superti-Furga Andrea |
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Institution: | 1Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, POB 9101, 6500 HB Nijmegen, The Netherlands;2Division of Pediatric Genetics, Centre for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79106 Freiburg, Germany;3Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland;4Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland;5Department of Biochemistry, University of Pavia, 27100 Pavia, Italy;6Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands;7Center for Prenatal Diagnosis, Kurfürstendamm 199, 10719 Berlin, Germany;8Amrita Institute Of Medical Sciences and Research Centre, Cochin, Kerala, India;9Department of Pediatrics, Medical College, Calicut, Kerala, India |
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Abstract: | We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints. |
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