Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms.
Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms.
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DOI：
10.1111/j.1600-0625.2008.00795.x
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发表时间：
2009-01
影响因子：
3.6
通讯作者：
Uitto J
中科院分区：
文献类型：
--
作者：
Li Q;Jiang Q;Pfendner E;Váradi A;Uitto J
弹性纤维假黄瘤（Pseudoxanthoma elasticum，PXE）是一种遗传性多系统疾病，以结缔组织的病理性矿化为特征，主要临床表现在皮肤、眼睛和心血管系统。致病基因最初被鉴定为ABCC 6，其编码主要在肝脏和肾脏中表达的ABC转运蛋白（ABCC 6）。ABCC 6在异位矿化中的关键作用已通过Abcc 6-/-敲除小鼠的发育得到证实，其概括了PXE的结缔组织矿化特征。ABCC 6中超过1000个突变等位基因的200多个不同的功能丧失突变的代表已被确定在这种常染色体隐性遗传病的简化突变检测策略。最近，GGCX基因的错义突变，无论是在复合杂合状态或双基因与复发性ABCC 6无义突变（p.R1141X），已被确定在PXE样皮肤表现和维生素K依赖性凝血因子缺乏症的患者。GGCX编码一种羧化酶，可催化凝血因子以及基质gla蛋白（MGP）的γ-谷氨酰羧化，基质gla蛋白（MGP）以完全羧化形式作为病理性矿化的全身性抑制剂。总的来说，这些观察结果表明ABCC 6基因功能缺失突变的结果是MGP的维生素K依赖性γ-谷氨酰羧化减少，随后是结缔组织矿化。进一步了解PXE的详细病理机制的进展应提供新的策略，以抵消，也许治愈，这种复杂的遗传性疾病的基因组环境界面。
Pseudoxanthoma elasticum (PXE), a prototype of heritable multi-system disorders, is characterized by pathologic mineralization of connective tissues, with primary clinical manifestations in the skin, eyes and the cardiovascular system. The causative gene was initially identified as ABCC6 which encodes an ABC transporter protein (ABCC6) expressed primarily in the liver and the kidneys. The critical role of ABCC6 in ectopic mineralization has been confirmed by the development of Abcc6-/- knock-out mice which recapitulate the features of connective tissue mineralization characteristic of PXE. Over 200 distinct loss-of-function mutations representative of over 1000 mutant alleles in ABCC6 have been identified by streamlined mutation detection strategies in this autosomal recessive disease. More recently, missense mutations in the GGCX gene, either in compound heterozygous state or digenic with a recurrent ABCC6 nonsense mutation (p.R1141X), have been identified in patients with PXE-like cutaneous findings and vitamin K-dependent coagulation factor deficiency. GGCX encodes a carboxylase which catalyzes γ-glutamyl carboxylation of coagulation factors as well as of matrix gla protein (MGP) which in fully carboxylated form serves as a systemic inhibitor of pathologic mineralization. Collectively, these observations suggest the hypothesis that a consequence of loss-of-function mutations in the ABCC6 gene is the reduced vitamin K-dependent γ-glutamyl carboxylation of MGP, with subsequent connective tissue mineralization. Further progress in understanding the detailed pathomechanisms of PXE should provide novel strategies to counteract, and perhaps cure, this complex heritable disorder at the genome-environment interface.
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影响因子：
3.6
作者：
LaRusso, Jennifer;Jiang, Qiujie;Uitto, Jouni
通讯作者：
Uitto, Jouni
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：
64.8
作者：
Dawson, Roger J. P.;Locher, Kaspar P.
通讯作者：
Locher, Kaspar P.
影响因子：
4.3
作者：
Borst, Piet;van de Wetering, Koen;Schlingemann, Reinier
通讯作者：
Schlingemann, Reinier