Pseudoxanthoma elasticum: molecular genetics and putative pathomechanisms.
Pseudoxanthoma elasticum: molecular genetics and putative pathomechanisms.
复制标题
DOI：
10.1038/jid.2009.411
复制
发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
弹性假性黄瘤（PXE）是一种典型的遗传性疾病，伴有异位矿化，表现为特征性的皮肤表现，眼部受累和心血管问题，具有相当高的发病率和死亡率。PXE的典型形式是由于ABCC6基因的功能缺失突变，该基因编码ABCC6， ABCC6是一种主要在肝脏表达的跨膜外排转运体。一些证据表明PXE是一种原发性代谢紊乱，在缺乏ABCC6转运蛋白活性的情况下，由于胎蛋白a和基质玻璃蛋白（MGP）水平降低，血浆抗矿化能力降低。MGP需要通过γ-谷氨酰羧化反应（一种维生素k依赖性反应）激活，以在外周结缔组织细胞中发挥抗矿化作用。虽然在体内通过ABCC6从肝细胞转运到循环系统的分子仍未被确定，但有假设认为，一种关键的维生素K衍生物，如与谷胱甘肽结合的还原性维生素K，是在缺乏ABCC6转运体活性的情况下，生理分泌到循环系统的。因此，γ-谷氨酰羧化酶对MGP的激活减弱，导致PXE结缔组织特征的缓慢但渐进的矿化。了解PXE的病理机制细节为开发针对这种目前难治性疾病的靶向分子疗法提供了基础。
Pseudoxanthoma elasticum (PXE), a prototypic heritable disorder with ectopic mineralization, manifests with characteristic skin findings, ocular involvement and cardiovascular problems, with considerable morbidity and mortality. The classic forms of PXE are due to loss-of-function mutations in the ABCC6 gene, which encodes ABCC6, a transmembrane efflux transporter expressed primarily in the liver. Several lines of evidence suggest that PXE is a primary metabolic disorder which, in the absence of ABCC6 transporter activity, displays reduced plasma anti-mineralization capacity due to reduced fetuin-A and matrix gla-protein (MGP) levels. MGP requires to be activated by γ-glutamyl carboxylation, a vitamin K-dependent reaction, to serve in anti-mineralization role in the peripheral connective tissue cells. While the molecules transported from the hepatocytes to circulation by ABCC6 in vivo remain unidentified, it has been hypothesized that a critical vitamin K derivative, such as reduced vitamin K conjugated with glutathione, is secreted to circulation physiologically, but not in the absence of ABCC6 transporter activity. As a result, activation of MGP by γ-glutamyl carboxylase is diminished, allowing slow, yet progressive, mineralization of connective tissues characteristic of PXE. Understanding of the pathomechanistic details of PXE provides a basis for development of targeted molecular therapies for this, currently intractable, disease.
登录
查看更多内容
影响因子：
3.5
作者：
Gorgels, TGMF;Hu, XF;Bergen, AAB
通讯作者：
Bergen, AAB
影响因子：
13.8
作者：
Baccarani-Contri, M;Bacchelli, B;Pasquali-Ronchetti, I
通讯作者：
Pasquali-Ronchetti, I
影响因子：
10.3
作者：
Bercovitch, L;Leroux, T;Weinstock, MA
通讯作者：
Weinstock, MA
影响因子：
4.3
作者：
Goral, Vedat;Demir, Dogan;Uyar, Asur
通讯作者：
Uyar, Asur
影响因子：
4.3
作者：
Borst, Piet;van de Wetering, Koen;Schlingemann, Reinier
通讯作者：
Schlingemann, Reinier