Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy
Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy
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DOI：
10.1093/rheumatology/keq048
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发表时间：
2010-06-01
期刊：
影响因子：
5.5
通讯作者：
Bonthron, David T.
中科院分区：
文献类型：
--
作者：
Diggle, Christine P.;Carr, Ian M.;Bonthron, David T.
目标。编码15-羟基前列腺素脱氢酶的15-羟基前列腺素脱氢酶（HPGD）基因的纯合隐性种系突变导致循环PGE(2)水平持续升高，导致原发性肥厚性骨关节病（PHO）综合征。迄今为止，在10个家庭中报道了纯合子HPGD突变，除了一个家庭外，其他家庭都显示亲本血缘关系。这些家庭中只有两个是欧洲血统。我们希望确定HPGD在非近亲欧洲家庭中引起PHO的作用。5个以前未报道的欧洲高加索家族，有一个或多个个体患有典型的PHO，通过对HPGD编码外显子的完整测序进行了临床鉴定。在所有五个家族的受影响个体中发现了双等位基因HPGD突变，证实了这种表型与HPGD突变的非常特定的关联。先前描述的c. 175_176delCT移码突变被观察到与相邻单核苷酸多态性的两个不同等位基因相关。在大多数典型的PHO患者中发现双等位基因HPGD突变，对于以这种方式出现的患者，特别是在儿童时期，HPGD基因测序是一项高度特异性的一线调查。c. 175_176delCT移码突变似乎是复发性的，并且是高加索家族中最常见的HPGD突变。
Objective. Homozygous recessive germline mutations of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene, encoding 15-hydroxyprostaglandin dehydrogenase, result in persistent elevation of circulating PGE(2) levels, causing the syndrome of primary hypertrophic osteoarthropathy (PHO). Homozygous HPGD mutations have so far been reported in 10 families, all but one displaying parental consanguinity. Only two of these families were of European origin. We wished to determine the role of HPGD in causing PHO in non-consanguineous European families.Methods. Five previously unreported families of Caucasian European origin, with one or more individuals affected with typical PHO, were characterized clinically and by complete sequencing of the HPGD coding exons.Results. Biallelic HPGD mutations were identified in affected individuals in all the five families, confirming a very specific association of this phenotype with HPGD mutations. The previously described c. 175_176delCT frameshift mutation was observed in association with two different alleles of an adjacent single nucleotide polymorphism.Conclusions. Biallelic HPGD mutations are found in the majority of patients with typical PHO, and sequencing of the HPGD gene is a highly specific first-line investigation for patients presenting in this way, particularly during childhood. The c. 175_176delCT frameshift mutation appears to be recurrent and to be the commonest HPGD mutation in Caucasian families.