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

Author

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  • Qiaochu Wang

    (Beijing Pediatric Research Institute
    Capital Medical University
    Capital Medical University, National Center for Children’s Health)

  • Zengge Wang

    (Beijing Pediatric Research Institute
    Capital Medical University
    Capital Medical University, National Center for Children’s Health)

  • Yizhen Wang

    (Beijing Pediatric Research Institute
    Capital Medical University
    Capital Medical University, National Center for Children’s Health)

  • Zhan Qi

    (Beijing Pediatric Research Institute
    Capital Medical University
    Capital Medical University, National Center for Children’s Health)

  • Dayong Bai

    (Capital Medical University; National Center for Children’s Health)

  • Chentong Wang

    (Beijing Pediatric Research Institute
    Capital Medical University
    Capital Medical University, National Center for Children’s Health)

  • Yuanying Chen

    (Beijing Pediatric Research Institute
    Capital Medical University
    Capital Medical University, National Center for Children’s Health)

  • Wenjian Xu

    (Beijing Pediatric Research Institute
    Capital Medical University
    Capital Medical University, National Center for Children’s Health)

  • 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
    Capital Medical University
    Capital Medical University, National Center for Children’s Health)

  • Michael Xi Zhu

    (The University of Texas Health Science Center at Houston)

  • Aihua Wei

    (Capital Medical University)

  • Wei Li

    (Beijing Pediatric Research Institute
    Capital Medical University)

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.

Suggested Citation

  • 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, 2023. "A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35786-9
    DOI: 10.1038/s41467-023-35786-9
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    References listed on IDEAS

    as
    1. Jennifer Y. Lin & David E. Fisher, 2007. "Melanocyte biology and skin pigmentation," Nature, Nature, vol. 445(7130), pages 843-850, February.
    2. Peter J. Calcraft & Margarida Ruas & Zui Pan & Xiaotong Cheng & Abdelilah Arredouani & Xuemei Hao & Jisen Tang & Katja Rietdorf & Lydia Teboul & Kai-Ting Chuang & Peihui Lin & Rui Xiao & Chunbo Wang &, 2009. "NAADP mobilizes calcium from acidic organelles through two-pore channels," Nature, Nature, vol. 459(7246), pages 596-600, May.
    3. Austin R. Graves & Patricia K. Curran & Carolyn L. Smith & Joseph A. Mindell, 2008. "The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes," Nature, Nature, vol. 453(7196), pages 788-792, June.
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