Rozeman Leida B, Sangiorgi Luca, Briaire-de Bruijn Inge H, Mainil-Varlet Pierre, Bertoni F, Cleton-Jansen Anne Marie, Hogendoorn Pancras C W, Bovée Judith V M G
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Hum Mutat. 2004 Dec;24(6):466-73. doi: 10.1002/humu.20095.
Enchondromatosis (Ollier disease, Maffucci syndrome) is a rare developmental disorder characterized by multiple enchondromas. Not much is known about its molecular genetic background. Recently, an activating mutation in the parathyroid hormone receptor type 1 (PTHR1) gene, c.448C>T (p.R150C), was reported in two of six patients with enchondromatosis. The mutation is thought to result in upregulation of the IHH/PTHrP pathway. This is in contrast to previous studies, showing downregulation of this pathway in other cartilaginous tumors. Therefore, we investigated PTHR1 in enchondromas and chondrosarcomas from 31 enchondromatosis patients from three different European countries, thereby excluding a population bias. PTHR1 protein expression was studied using immunohistochemistry, revealing normal expression. The presence of the described PTHR1 mutation was analyzed, using allele-specific oligonucleotide hybridization confirmed by sequence analysis, in tumors from 26 patients. In addition, 11 patients were screened for other mutations in the PTHR1 gene by sequence analysis. Using both allele-specific oligonucleotide hybridization and sequencing, we could neither confirm the previously found mutation nor find any other mutations in the PTHR1 gene. These results indicate that the PTHR1 gene is not, in contrast to previous suggestions, the culprit for enchondromatosis.
内生软骨瘤病（Ollier病、Maffucci综合征）是一种罕见的发育障碍，其特征为多发内生软骨瘤。关于其分子遗传背景，人们了解甚少。最近，在6例内生软骨瘤病患者中有2例被报道甲状旁腺激素1型受体（PTHR1）基因发生激活突变，即c.448C>T（p.R150C）。该突变被认为导致IHH/PTHrP信号通路上调。这与之前的研究相反，之前的研究显示该信号通路在其他软骨肿瘤中下调。因此，我们对来自三个不同欧洲国家的31例内生软骨瘤病患者的内生软骨瘤和软骨肉瘤中的PTHR1进行了研究，从而排除了群体偏差。采用免疫组化研究PTHR1蛋白表达，结果显示表达正常。使用等位基因特异性寡核苷酸杂交并经序列分析证实，对26例患者肿瘤中所述PTHR1突变的存在情况进行了分析。此外，通过序列分析对11例患者的PTHR1基因其他突变进行了筛查。使用等位基因特异性寡核苷酸杂交和测序，我们既无法证实先前发现的突变，也未在PTHR1基因中发现任何其他突变。这些结果表明，与之前的推测相反，PTHR1基因并非内生软骨瘤病的病因。
