Hypomyelinating leukodystrophy-associated missense mutant of FAM126A/hyccin/DRCTNNB1A aggregates in the endoplasmic reticulum
Hypomyelinating leukodystrophy-associated missense mutant of FAM126A/hyccin/DRCTNNB1A aggregates in the endoplasmic reticulum
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DOI：
10.1016/j.jocn.2013.09.014
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发表时间：
2014-06-01
影响因子：
2
通讯作者：
Yamauchi, Junji
中科院分区：
文献类型：
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作者：
Miyamoto, Yuki;Torii, Tomohiro;Yamauchi, Junji
髓鞘减少性白质营养不良(HLD)是一种遗传性中枢神经系统疾病，髓鞘不能正常形成。这种疾病的原型是X连锁隐性Pelizaeus-Merzbacher病(现在也称为HLD1)，它是由plp1基因的突变、倍增或缺失引起的。PLP1错义突变导致蛋白质聚集和聚集在内质网(ER)等亚细胞内。一种名为HLD5的常染色体隐性遗传性Pelizaeus-Merzbacher样疾病的基因被命名为Fam126a(也称为hyccin或drctnnb1a)。虽然基因突变经常导致FAM126A蛋白质缺乏，但一种已知的错义突变Leu-53-to-Pro(L53P)允许产生一些蛋白质。在这里，我们表明L53P突变体聚集在细胞中，主要积累在内质网中。这与野生型FAM126A相反，野生型FAM126A分布在细胞质中。此外，L53P突变体的表达促进了参与未折叠蛋白反应的激酶的活性。这些结果表明，与疾病相关的FAM126A错义突变导致亚细胞内蛋白质积累，可能介导与疾病相关的表型，这与PLP1相似。(C)2013爱思唯尔有限公司。保留所有权利。
Hypomyelinating leukodystrophies (HLD) are hereditary central nervous system diseases in which the myelin sheath does not form properly. The disease prototype is the X-linked recessive Pelizaeus-Merzbacher disease (also now known as HLD1), which is caused by the mutation, multiplication, or deletion of the plp1 gene. PLP1 missense mutations lead to protein aggregation and accumulation in subcellular compartments such as the endoplasmic reticulum (ER). The gene responsible for an autosomal recessive Pelizaeus-Merzbacher-like disease called HLD5 is named fam126a (also known as hyccin or drctnnb1a). While the gene mutations often cause FAM126A protein deficiency, one known missense mutation, Leu-53-to-Pro (L53P), allows some protein to be produced. Here, we show that the L53P mutant aggregates in cells, accumulating primarily in the ER. This is in contrast to the wild type FAM126A, which distributes throughout the cytoplasm. In addition, the L53P mutant expression promotes the activities of kinases involved in unfolded protein response. These results suggest that a disease-associated FAM126A missense mutation causes protein accumulation in subcellular compartments, possibly to mediate a disease-associated phenotype, which is similar to what is seen with PLP1. (C) 2013 Elsevier Ltd. All rights reserved.