GJC2 Missense Mutations Cause Human Lymphedema
GJC2 Missense Mutations Cause Human Lymphedema
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DOI：
10.1016/j.ajhg.2010.04.010
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发表时间：
2010-06-11
影响因子：
9.8
通讯作者：
Finegold, David N.
中科院分区：
文献类型：
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作者：
Ferrell, Robert E.;Baty, Catherine J.;Finegold, David N.
淋巴水肿是淋巴结构或功能缺陷的临床表现。在调节淋巴发育的基因中发现突变会导致遗传性淋巴水肿。目前还没有发现介导淋巴功能的基因突变，这些基因会导致遗传性淋巴水肿。比较淋巴管和血液内皮细胞的调查微阵列研究确定了淋巴管内皮细胞中几种连接蛋白的表达。此外，缝隙连接与维持淋巴流动有关。通过对一组以遗传性淋巴水肿为主的家系进行GJA1、GJA4和GJC2的测序，我们发现了6个GJC2(编码连接蛋白[CX]47)具有独特错义突变的先证者。两个较大的家系合并淋巴水肿和GJC2突变(LOD评分=6.5)。我们假设GJC2的错义突变改变了缝隙连接功能，并扰乱了淋巴途径。到目前为止，GJC2突变只被认为会导致髓鞘功能障碍，Cx47的主要表达仅限于中枢神经系统。GJC2突变是原发性淋巴水肿的原因之一，这增加了新型缝隙连接修饰剂作为某些形式淋巴水肿潜在治疗方法的可能性。
Lymphedema is the clinical manifestation of defects in lymphatic structure or function. Mutations identified in genes regulating lymphatic development result in inherited lymphedema. No mutations have yet been identified in genes mediating lymphatic function that result in inherited lymphedema. Survey microarray studies comparing lymphatic and blood endothelial cells identified expression of several connexins in lymphatic endothelial cells. Additionally, gap junctions are implicated in maintaining lymphatic flow. By sequencing GJA1, GJA4, and GJC2 in a group of families with dominantly inherited lymphedema, we identified six probands with unique missense mutations in GJC2 (encoding connexin [Cx] 47). Two larger families cosegregate lymphedema and GJC2 mutation (LOD score = 6.5). We hypothesize that missense mutations in GJC2 alter gap junction function and disrupt lymphatic How. Until now, GJC2 mutations were only thought to cause dysmyelination, with primary expression of Cx47 limited to the central nervous system. The identification of GJC2 mutations as a cause of primary lymphedema raises the possibility of novel gap-junction-modifying agents as potential therapy for some forms of lymphedema.