Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis
Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis
复制标题
DOI：
10.1002/humu.22111
复制
发表时间：
2012-08-01
期刊：
影响因子：
3.9
通讯作者：
Bonthron, David T.
中科院分区：
文献类型：
--
作者：
Diggle, Christine P.;Parry, David A.;Bonthron, David T.
厚皮骨膜病，或原发性肥大性骨关节病（PHO），是一种遗传性多系统疾病，其特征非常类似于反应性骨关节病，通常伴随肿瘤和炎症病理。我们以前描述的缺陷的前列腺素降解酶15-羟基前列腺素脱氢酶（HPGD）作为这种情况的原因，牵连升高的循环前列腺素E2（PGE 2）作为PHO的病因，也许也作为次要HO的主要介质。然而，PHO是遗传异质性的。在这里，我们使用全外显子组测序，以确定前列腺素转运蛋白SLCO 2A 1的隐性突变，在个人缺乏HPGD突变。我们对4名重度PHO先证者进行了外显子组测序，然后对另外9名先证者进行了SLCO 2A 1的常规突变分析。双等位基因SLCO 2A 1突变在13个家庭中的12个。受影响的个体尿PGE 2升高，但与HPGD缺乏的患者不同，也排出大量的PGE 2代谢产物PGE-M。还确定了两组之间的临床差异，特别是SLCO 2A 1缺陷个体由于骨髓纤维化而具有高频率的严重贫血。这些发现加强了全身或局部前列腺素过量作为HO刺激的关键作用。他们还表明，前列腺素诱导或维持造血干细胞可能取决于转运蛋白活性。Mutat 33：11751181，2012。(c)2012 Wiley Periodicals，Inc.
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.