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Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome)


Studying consanguineous families with Ghosal hematodiaphyseal dysplasia syndrome (GHDD), a disorder of increased bone density, we identified mutations in TBXAS1, which encodes thromboxane synthase (TXAS). TXAS, an enzyme of the arachidonic acid cascade, produces thromboxane A2 (TXA2). Platelets from subjects with GHDD showed a specific deficit in arachidonic acid–produced aggregation. We also found that TXAS and TXA2 modulated expression of TNFSF11 and TNFRSF11B (encoding RANKL and osteoprotegerin (OPG), respectively) in primary cultured osteoblasts.

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Figure 1: TXAS and TXA2 modulate the TNFSF11 pathway.
Figure 2: Platelet studies.


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We thank the subjects and their families for their support. We thank D. Rabier, M. Dechaux and O. Boccara from the Necker-Enfants Malades Hospital for technical support and D. Renier from the Necker-Enfants Malades Hospital for providing normal cranial sutures.

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Authors and Affiliations



D.G. and B.I. performed the sequence analysis; V.P. and M.D. performed the platelet exocytosis studies; V.S. performed the three-dimensional modeling of TXAS; D.G. and F.D. performed the real-time quantitative PCR analysis; C.P., C.V.-S., B.B.-M., S. Blanche, M.-C.d.V., M.L.M. and V.C.-D. provided clinical data; D.G., S. Bellaris and L.L.-M. performed primary osteoblast cultures; A.-M.F. and P.G. performed the platelet aggregation studies; D.G. and S. Bellaris performed the ELISA; and D.G., A.M. and V.C.-D. designed the experiment and wrote the manuscript.

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Correspondence to Valérie Cormier-Daire.

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Supplementary Figures 1–4, Supplementary Tables 1–2, Supplementary Methods (PDF 1746 kb)

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Geneviève, D., Proulle, V., Isidor, B. et al. Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome). Nat Genet 40, 284–286 (2008).

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