A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P(2) and causes lysosome acidification and hypopigmentation.
A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P(2) and causes lysosome acidification and hypopigmentation.
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DOI：
10.1038/s41467-023-35786-9
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发表时间：
2023-01-14
影响因子：
16.6
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Wang, Qiaochu;Wang, Zengge;Wang, Yizhen;Qi, Zhan;Bai, Dayong;Wang, Chentong;Chen, Yuanying;Xu, Wenjian;Zhu, Xili;Jeon, Jaepyo;Xiong, Jian;Hao, Chanjuan;Zhu, Michael Xi;Wei, Aihua;Li, Wei
白化病是一组遗传性疾病，主要影响皮肤、头发和眼睛。在这里，我们发现了白化病患者Tpcn2基因中的一个新的点突变p.R210C，该基因编码两个孔道2(TPC2)。TPC2是一种内溶酶体和黑素体定位的非选择性阳离子通道，参与调节色素的产生。通过靶向TPC2的质膜记录和扩大的内溶酶体空泡的直接记录，我们发现R210C突变体表现出结构性通道激活，并显著增加了对PI(3，5)P2的亲和力。携带同源突变R194C的小鼠也表现出皮毛和皮肤的色素减少，视网膜中的色素和黑素小体以显性遗传方式减少。此外，携带R194C突变的小鼠胚胎成纤维细胞显示内溶酶体增大、溶酶体钙释放增加和超酸化。我们的数据表明，R210C是一种致病的功能获得TPC2变体，它是一种不寻常的显性白化类型的基础。TPC2是一种重要的细胞器Na+/Ca~(2+)释放通道，调节溶酶体及其相关细胞器的功能。在这里，王等人。证明TPC2的功能获得突变(R210C)会导致色素减少、内溶酶体增大、溶酶体钙释放增加和高酸化。
Albinism is a group of inherited disorders mainly affecting skin, hair and eyes. Here we identify a de novo point mutation, p.R210C, in the TPCN2 gene which encodes Two Pore Channel 2 (TPC2) from a patient with albinism. TPC2 is an endolysosome and melanosome localized non-selective cation channel involved in regulating pigment production. Through inside-out recording of plasma membrane targeted TPC2 and direct recording of enlarged endolysosomal vacuoles, we reveal that the R210C mutant displays constitutive channel activation and markedly increased affinity to PI(3,5)P2. Mice harboring the homologous mutation, R194C, also exhibit hypopigmentation in the fur and skin, as well as less pigment and melanosomes in the retina in a dominant inheritance manner. Moreover, mouse embryonic fibroblasts carrying the R194C mutation show enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification. Our data suggest that R210C is a pathogenic gain-of-function TPC2 variant that underlies an unusual dominant type of albinism. TPC2 is an important organellar Na+/Ca2+ release channel which regulates function of lysosomes and lysosome-related organelles. Here, Wang et al. demonstrate that a gain-of-function mutation (R210C) in TPC2 leads to hypopigmentaion, enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification.
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影响因子：
16.6
作者：
Dong, Xian-ping;Shen, Dongbiao;Wang, Xiang;Dawson, Taylor;Li, Xinran;Zhang, Qi;Cheng, Xiping;Zhang, Yanling;Weisman, Lois S.;Delling, Markus;Xu, Haoxing
通讯作者：
Xu, Haoxing
影响因子：
4.5
作者：
Böck J;Krogsaeter E;Passon M;Chao YK;Sharma S;Grallert H;Peters A;Grimm C
通讯作者：
Grimm C
影响因子：
64.8
作者：
Graves, Austin R.;Curran, Patricia K.;Mindell, Joseph A.
通讯作者：
Mindell, Joseph A.
DOI：
10.1073/pnas.1705739114
发表时间：
2017-10-10
影响因子：
11.1
作者：
Chao, Yu-Kai;Schludi, Verena;Grimm, Christian
通讯作者：
Grimm, Christian
影响因子：
13.7
作者：
Kuht, Helen J.;Maconachie, Gail D. E.;Han, Jinu;Kessel, Line;van Genderen, Maria M.;McLean, Rebecca J.;Hisaund, Michael;Tu, Zhanhan;Hertle, Richard W.;Gronskov, Karen;Bai, Dayong;Wei, Aihua;Li, Wei;Jiao, Yonghong;Smirnov, Vasily;Choi, Jae-Hwan;Tobin, Martin D.;Sheth, Viral;Purohit, Ravi;Dawar, Basu;Girach, Ayesha;Strul, Sasha;May, Laura;Chen, Fred K.;Jeffery, Rachael C. Heath;Aamir, Abdullah;Sano, Ronaldo;Jin, Jing;Brooks, Brian P.;Kohl, Susanne;Arveiler, Benoit;Montoliu, Lluis;Engle, Elizabeth C.;Proudlock, Frank A.;Nishad, Garima;Pani, Prateek;Varma, Girish;Gottlob, Irene;Thomas, Mervyn G.
通讯作者：
Thomas, Mervyn G.