Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Lab Invest. 2010 Jun;90(6):895-905. doi: 10.1038/labinvest.2010.68. Epub 2010 Apr 5.
Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE.
软组织矿化是一个受到严格调控的过程，依赖于全身性和组织特异性钙沉淀抑制剂和促进剂的活性。其中许多物质，如基质 Gla 蛋白 (MGP) 和骨钙素 (OC)，需要经过羧化作用才能发挥活性。这种翻译后修饰由γ-谷氨酰羧化酶 GGCX 催化，需要维生素 K (VK) 作为必需的辅助因子。最近，我们描述了一种新的表型，其特征是弹性纤维的异常矿化，这是由 GGCX 突变引起的。由于其与弹性纤维矿化的典型疾病假性黄色瘤病 (PXE) 的相似性，因此被命名为 PXE 样综合征。由于 GGCX 的突变会降低蛋白的羧化作用，因此无活性的钙化抑制剂可能会导致 PXE 样综合征中的异位矿化。由于与 PXE 具有显著的相似性，我们使用创新的、构象特异性抗体，对 PXE 样和 PXE 患者的血清、血浆（使用 ELISA）和皮肤组织（使用免疫组织化学）中的各种形式的 VK 依赖性蛋白进行了比较研究。此外，我们还使用 HPLC 测量了 PXE 样和 PXE 样本中的 VK 血清浓度，以评估 VK 状态。在 PXE 样患者中，我们注意到未羧化的 Gla 蛋白、MGP 和 OC 在血浆、血清和真皮中积累。这些患者的血清 VK 水平正常。在 PXE 患者中，我们发现循环和皮肤组织中的 Gla 蛋白存在类似但不完全相同的结果。然而，与对照组相比，PXE 患者的 VK 血清浓度显著降低。我们的研究结果表明，PXE 样综合征和 PXE 中的异位矿化是由于 VK 依赖性钙化抑制剂的蛋白羧化作用不足引起的。虽然在 PXE 样患者中，这是由于 GGCX 基因突变所致，但 VK 羧化辅助因子的缺乏是 PXE 中钙化抑制剂活性降低的基础。
