Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis

被引:72
作者
Diggle, Christine P. [1 ]
Parry, David A. [1 ]
Logan, Clare V. [1 ]
Laissue, Paul [2 ,3 ]
Rivera, Carolina [2 ]
Martin Restrepo, Carlos [2 ,3 ]
Fonseca, Dora J. [2 ,3 ]
Morgan, Joanne E. [1 ]
Allanore, Yannick [4 ]
Fontenay, Michaela [5 ]
Wipff, Julien [4 ]
Varret, Mathilde [6 ]
Gibault, Laure [7 ]
Dalantaeva, Nadezhda [8 ,9 ]
Korbonits, Marta [8 ]
Zhou, Bowen [10 ]
Yuan, Gang [11 ]
Harifi, Ghita [12 ]
Cefle, Kivanc [13 ]
Palanduz, Sukru [13 ]
Akoglu, Hadim [14 ]
Zwijnenburg, Petra J. [15 ]
Lichtenbelt, Klaske D. [16 ]
Aubry-Rozier, Berengere [17 ,18 ]
Superti-Furga, Andrea [19 ]
Dallapiccola, Bruno [20 ]
Accadia, Maria [21 ]
Brancati, Francesco [22 ,23 ,24 ]
Sheridan, Eamonn G. [1 ]
Taylor, Graham R. [1 ]
Carr, Ian M. [1 ]
Johnson, Colin A. [1 ]
Markham, Alexander F. [1 ]
Bonthron, David T. [1 ]
机构
[1] Univ Leeds, Sch Med, Leeds LS9 7TF, W Yorkshire, England
[2] Univ Rosario, Unidad Genet, Escuela Med Ciencias Salud, Bogota, Colombia
[3] Genet Mol Colombia, Bogota, Colombia
[4] Paris Descartes Univ, Dept Rheumatol A, Cochin Hosp, APHP,INSERM,U1016, Paris, France
[5] INSERM, U1016, Inst Cochin, Dept Immunol & Hematol,CNRS,UMR 8104, Paris, France
[6] Hop Xavier Bichat, INSERM, U698, Paris, France
[7] Hop Cochin, Serv Anat Pathol, F-75674 Paris, France
[8] Queen Mary Univ London, Ctr Endocrinol, Barts & London Sch Med & Dent, London, England
[9] Res Ctr Endocrinol, Dept Neuroendocrinol, Moscow, Russia
[10] Jianghan Univ, Hosp Wuhan 6, Dept Endocrinol, Wuhan, Peoples R China
[11] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Endocrinol, Wuhan 430074, Peoples R China
[12] Mohammed VI Med Ctr, Dept Rheumatol, Marrakech, Morocco
[13] Istanbul Fac Med, Dept Internal Med, Div Med Genet, Istanbul, Turkey
[14] Ankara Numune Training & Res Hosp, Dept Nephrol, Ankara, Turkey
[15] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands
[16] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands
[17] CHU Vaudois, Rheumatol Dept, Lausanne, Switzerland
[18] CHU Vaudois, Bone Dis Ctr, Lausanne, Switzerland
[19] Univ Lausanne, Dept Pediat, Lausanne, Switzerland
[20] Bambino Gesu Pediat Hosp, Ist Ricovero & Cura Carattere Sci, Rome, Italy
[21] Vito Fazzi Hosp, Med Genet Lab, Lecce, Italy
[22] Gabriele dAnnunzio Univ Fdn, Chieti, Italy
[23] Casa Sollievo Sofferenza Mendel Inst, Rome, Italy
[24] Tor Vergata Univ, Depat Biopathol & Diagnost Imaging, Rome, Italy
关键词
prostaglandin; osteoarthropathy; genetics; myelofibrosis; SLC02A1; PRIMARY HYPERTROPHIC OSTEOARTHROPATHY; HEMATOPOIETIC STEM-CELL; DNA-SEQUENCING DATA; DEHYDROGENASE; FRAMEWORK; RELEASE; DISEASE; GENE;
D O I
10.1002/humu.22111
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E2 (PGE2) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE2, but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE2 metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity. Hum Mutat 33:11751181, 2012. (c) 2012 Wiley Periodicals, Inc.
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页码:1175 / 1181
页数:7
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