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Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8595-E8602. doi: 10.1073/pnas.1705739114. Epub 2017 Sep 18.

TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms.

Author information

1
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
2
High-Performance and Cloud Computing Group, Zentrum für Datenverarbeitung, Universität Tübingen, 72076 Tübingen, Germany.
3
Department of Dermatology, Medical Faculty, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
4
Calcium Signals Laboratory, Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
5
Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; christian.wahl@cup.uni-muenchen.de christian.grimm@cup.uni-muenchen.de.

Abstract

Two-pore channels (TPCs) are endolysosomal cation channels. Two members exist in humans, TPC1 and TPC2. Functional roles associated with the ubiquitously expressed TPCs include VEGF-induced neoangiogenesis, LDL-cholesterol trafficking and degradation, physical endurance under fasting conditions, autophagy regulation, the acrosome reaction in sperm, cancer cell migration, and intracellular trafficking of pathogens such as Ebola virus or bacterial toxins (e.g., cholera toxin). In a genome-wide association study for variants associated with human pigmentation characteristics two coding variants of TPC2, rs35264875 (encoding M484L) and rs3829241 (encoding G734E), have been found to be associated with a shift from brown to blond hair color. In two recent follow-up studies a role for TPC2 in pigmentation has been further confirmed. However, these human polymorphic variants have not been functionally characterized until now. The development of endolysosomal patch-clamp techniques has made it possible to investigate directly ion channel activities and characteristics in isolated endolysosomal organelles. We applied this technique here to scrutinize channel characteristics of the polymorphic TPC2 variants in direct comparison with WT. We found that both polymorphisms lead to a gain of channel function by independent mechanisms. We next conducted a clinical study with more than 100 blond- and brown/black-haired individuals. We performed a genotype/phenotype analysis and subsequently isolated fibroblasts from WT and polymorphic variant carriers for endolysosomal patch-clamp experimentation to confirm key in vitro findings.

KEYWORDS:

TPC; TPC2; pigmentation; polymorphism; two-pore channel

PMID:
28923947
PMCID:
PMC5642689
DOI:
10.1073/pnas.1705739114
[Indexed for MEDLINE]
Free PMC Article

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