Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy
Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy
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DOI：
10.1038/ng.153
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发表时间：
2008-06-01
期刊：
影响因子：
30.8
通讯作者：
Bonthron, David T.
中科院分区：
文献类型：
--
作者：
Uppal, Sandeep;Diggle, Christine P.;Bonthron, David T.
希波克拉底在公元前世纪认识到的趾杵状变是肺肥大性骨关节病的外在标志，肺肥大性骨关节病是继发于各种获得性疾病（尤其是胸内肿瘤）的临床症状[1]。迄今为止，对杵状畸形和肥大性骨关节病的发病机制知之甚少，但认识到肥大性骨关节病（PHO）的一种临床上难以区分的原发性（特发性）形式（2，3）。这种家族性疾病可导致诊断混乱，以及严重的残疾。通过自体接合性方法，我们将PHO定位于染色体4 q33-q34，并鉴定了HPGD中的突变，该突变编码前列腺素降解的主要酶15-羟基前列腺素脱氢酶。纯合子个体发生继发于前列腺素E-2水平慢性升高的PHO。杂合子亲属也表现出较轻的生化和临床表现。这些发现不仅提示PHO的治疗，而且还暗示继发于其他病理的杵状变可能是前列腺素介导的。在不明原因的杵状畸形患者中进行HPGD突变检测和HPGD缺乏症的生化检测可能有助于广泛寻找隐匿性病理。
Digital clubbing, recognized by Hippocrates in the fifth century BC, is the outward hallmark of pulmonary hypertrophic osteoarthropathy, a clinical constellation that develops secondary to various acquired diseases, especially intrathoracic neoplasm(1). The pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of hypertrophic osteoarthropathy (PHO) is recognized(2,3). This familial disorder can cause diagnostic confusion, as well as significant disability. By autozygosity methods, we mapped PHO to chromosome 4q33-q34 and identified mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation. Homozygous individuals develop PHO secondary to chronically elevated prostaglandin E-2 levels. Heterozygous relatives also show milder biochemical and clinical manifestations. These findings not only suggest therapies for PHO, but also imply that clubbing secondary to other pathologies may be prostaglandin mediated. Testing for HPGD mutations and biochemical testing for HPGD deficiency in patients with unexplained clubbing might help to obviate extensive searches for occult pathology.