Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 88, Issue 5, Pages 608-615Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2011.04.002
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Funding
- Swiss National Science Foundation [FN 310030-132940/BONAFE Luisa]
- Fonds de Recherche du Departement Medico-Chirurgical de Pediatrie, CHUV, Lausanne
- German Bundesministerium fur Bildung und Forschung
- Deutsche Forschungsgemeinschaft [La 1381/1-3]
- Netherlands Organization for Health Research and Development (ZonMW) [917-66-363, 911-08-025, 916-86-016]
- Leenaards Foundation, Lausanne, Switzerland
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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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