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

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

  • Nat Commun. 2023 Jan 14;14(1):226. doi: 10.1038/s41467-023-35786-9.
Qiaochu Wang # 1 2 3,  Zengge Wang # 1 2 3,  Yizhen Wang 1 2 3,  Zhan Qi 1 2 3,  Dayong Bai 4,  Chentong Wang 1 2 3,  Yuanying Chen 1 2 3,  Wenjian Xu 1 2 3,  Xili Zhu 5,  Jaepyo Jeon 6,  Jian Xiong 6,  Chanjuan Hao 1 2 3,  Michael Xi Zhu 6,  Aihua Wei 7,  Wei Li 8 9
Affiliations

Affiliations

  • 1 Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing, China.
  • 2 MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China.
  • 3 Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
  • 4 Department of Ophthalmology, Beijing Children's Hospital, Capital Medical University; National Center for Children's Health, Beijing, China.
  • 5 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 6 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 7 Department of Dermatology, Tongren Hospital, Capital Medical University, Beijing, China. [email protected].
  • 8 Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing, China. [email protected].
  • 9 MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 36641477 DOI: 10.1038/s41467-023-35786-9
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.

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