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 A(2) (TXA(2)). Platelets from subjects with GHDD showed a specific deficit in arachidonic acid-produced aggregation. We also found that TXAS and TXA(2) modulated expression of TNFSF11 and TNFRSF11B (encoding RANKL and osteoprotegerin (OPG), respectively) in primary cultured osteoblasts.
Geneviève
David
D
Département de Génétique, Unité INSERM U781, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75015 Paris, France.
Proulle
Valérie
V
Isidor
Bertrand
B
Bellais
Samuel
S
Serre
Valérie
V
Djouadi
Fatima
F
Picard
Capucine
C
Vignon-Savoye
Capucine
C
Bader-Meunier
Brigitte
B
Blanche
Stéphane
S
de Vernejoul
Marie-Christine
MC
Legeai-Mallet
Laurence
L
Fischer
Anne-Marie
AM
Le Merrer
Martine
M
Dreyfus
Marie
M
Gaussem
Pascale
P
Munnich
Arnold
A
Cormier-Daire
Valérie
V
D019943:Amino Acid Substitution; D015519:Bone Density / Q000235:genetics; D001847:Bone Diseases / Q000097:blood / Q000235:genetics*; D016723:Bone Remodeling / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D002478:Cells, Cultured; D003241:Consanguinity; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D013928:Thromboxane A2 / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000097:blood / Q000235:genetics* / Q000502:physiology
D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase