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

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机构： [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 [5]National Center for Children’s Health, Beijing, China ,State KeyLaboratory of StemCell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [6]Department of Integrative Biology andPharmacology, 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

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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.© 2023. The Author(s).

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大类 | 1 区

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小类 | 1 区综合性期刊

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大类 | 1 区

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小类 | 1 区综合性期刊

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Q1 MULTIDISCIPLINARY SCIENCES

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Q1 MULTIDISCIPLINARY SCIENCES

影响因子： 14.7 最新[2023版] 16.1 最新五年平均 17.694 出版当年[2021版] 17.764 出版当年五年平均 14.919 出版前一年[2020版] 16.6 出版后一年[2022版]

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第一作者机构： [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

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通讯作者：

通讯机构： [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

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