A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation

Qiaochu Wang, Zengge Wang, Yizhen Wang, Zhan Qi, Dayong Bai, Chentong Wang, Yuanying Chen, Wenjian Xu, Xili Zhu, Jaepyo Jeon, Jian Xiong, Chanjuan Hao, Michael Xi Zhu, Aihua Wei () and Wei Li ()
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Qiaochu Wang: Beijing Pediatric Research Institute
Zengge Wang: Beijing Pediatric Research Institute
Yizhen Wang: Beijing Pediatric Research Institute
Zhan Qi: Beijing Pediatric Research Institute
Dayong Bai: Capital Medical University; National Center for Children’s Health
Chentong Wang: Beijing Pediatric Research Institute
Yuanying Chen: Beijing Pediatric Research Institute
Wenjian Xu: Beijing Pediatric Research Institute
Xili Zhu: Institute of Zoology, Chinese Academy of Sciences
Jaepyo Jeon: The University of Texas Health Science Center at Houston
Jian Xiong: The University of Texas Health Science Center at Houston
Chanjuan Hao: Beijing Pediatric Research Institute
Michael Xi Zhu: The University of Texas Health Science Center at Houston
Aihua Wei: Capital Medical University
Wei Li: Beijing Pediatric Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-35786-9

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