The Molecular Basis of Chemical Chaperone Therapy for Oculocutaneous Albinism Type 1A
The Molecular Basis of Chemical Chaperone Therapy for Oculocutaneous Albinism Type 1A
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DOI：
10.1016/j.jid.2018.10.033
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发表时间：
2019-05-01
影响因子：
6.5
通讯作者：
Fukai, Kazuyoshi
中科院分区：
文献类型：
--
作者：
Teramae, Ayako;Kobayashi, Yui;Fukai, Kazuyoshi
眼皮肤白化病（OCA）是一种常染色体隐性遗传疾病，其特征是皮肤、头发和眼睛中的黑色素减少或完全缺乏。目前尚无有效的治疗方法。1型OCA是由破坏酪氨酸酶（TYR）功能的突变引起的，酪氨酸酶是黑色素合成的限速酶。最近，它表明，酪氨酸酶在一些患者与OCA 1型突变是保留在内质网和它的催化活性丧失，一种现象称为内质网滞留。然而，据我们所知，酪氨酸酶的细胞内定位与OCA 1型错义突变的日本患者还没有报道。在这项研究中，我们首先研究了日本OCA 1A型错义突变酪氨酸酶的细胞内定位使用蛋白质印迹和免疫组织化学染色。R77Q、R239W、D383N和P431L突变体酪氨酸酶保留在内质网中，H211Y突变体酪氨酸酶部分转运到高尔基体。第二，我们探讨了化学伴侣治疗的可能性与OCA 1A型错义突变的日本患者，发现HeLa细胞表达P431L突变酪氨酸酶恢复酪氨酸酶活性治疗后，低剂量的酪氨酸酶抑制剂，作为化学伴侣，在剂量依赖性的方式。这些结果提供了一个可能的化学伴侣治疗的基础上，以恢复酪氨酸酶活性的OCA 1A型患者。
Oculocutaneous albinism (OCA) is an autosomal recessive disease characterized by the reduction or complete lack of melanin pigment in the skin, hair, and eyes. No effective treatment for OCA is available at present. OCA type 1 is caused by mutations that disrupt the function of tyrosinase (TYR), the rate-limiting enzyme of melanin synthesis. Recently, it was shown that tyrosinase in some patients with OCA type 1 mutation is retained in the endoplasmic reticulum and that its catalytic activity is lost, a phenomenon known as endoplasmic reticulum retention. However, to our knowledge, the intracellular localization of tyrosinase in Japanese patients with OCA type 1 missense mutations has not been reported. In this study, we first investigated the intracellular localization of Japanese OCA type 1A missense mutant tyrosinases using Western blotting and immunohistochemical staining. R77Q, R239W, D383N, and P431L mutant tyrosinases were retained in the endoplasmic reticulum, and H211Y mutant tyrosinase was partially transported to the Golgi apparatus. Second, we explored the possibility of chemical chaperone therapy for Japanese patients with OCA type 1A missense mutations and found that HeLa cells expressing P431L mutant tyrosinase have restored tyrosinase activity after treatment with a low-dose tyrosinase inhibitor, as a chemical chaperone, in a dose-dependent manner. These results provide the basis for a possible chemical chaperone therapy to recover tyrosinase activities in patients with OCA type 1A patients.