A Gain-of-Function TPC2 Variant R210C Increases Affinity to PI(3,5)P2 and Causes Lysosome Acidification and Hypopigmentation

Authors

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
Wei Li

Publication Date

1-14-2023

Journal

Nature Communications

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.

Keywords

Animals, Mice, Albinism, Fibroblasts, Gain of Function Mutation, Hydrogen-Ion Concentration, Lysosomes, Calcium Channels, Disease genetics, Homeostasis, Ion channels, Permeation and transport, Electrophysiology

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Associated Data

PMID: 36641477