{"doi":"10.1101/2021.02.05.430016","title":"The lysosomal chloride-proton exchanger CLC7 functions in melanosomes as a negative regulator of human pigmentation","abstract":"Abstract Mutations in the Cl − /H + exchanger CLC7 and its subunit OSTM1 result in osteopetrosis, lysosomal disorders, and pigmentation defects in mice and humans. How CLC7/OSTM1 regulates pigmentation in skin and hair melanocytes remains unexplored. In human epidermal melanocytes, we found CLC7/OSTM1 localized to melanosomes, the organelles in which melanin is synthesized, where it negatively regulates melanin production. Using a novel ratiometric melanosomal pH indicator, we showed that CLC7 acidifies melanosomes, opposing the function of the oculocutaneous albinism II (OCA2) Cl − ion channel. The de novo CLC7 variant (CLC7-Y715C) that causes albinism in humans and mice, decreased melanocytes pigmentation, which was restored by coexpression of OCA2. Remarkably, the enlarged hyperacidic vacuoles caused by CLC7-Y715C were also rescued by OCA2 coexpression in both melanocytes and non-melanocytic cells. Our data uncover a novel mechanism by which CLC7 regulates melanocyte pigmentation and identifies OCA2 as a tool to counteract the effects of CLC7 activating mutations.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215020,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":784632,"name":"Jessica L. Scales","orcid":"0000-0003-3608-1247","position":1,"is_corresponding":false},{"id":809238,"name":"Joshaya Trotman","orcid":"0000-0003-0483-0098","position":2,"is_corresponding":false},{"id":648330,"name":"Kazumasa Wakamatsu","orcid":"0000-0003-1748-9001","position":3,"is_corresponding":false},{"id":648340,"name":"Shosuke Ito","orcid":"0000-0001-9182-5144","position":4,"is_corresponding":false},{"id":274299,"name":"Elena Oancea","orcid":"0000-0001-9584-5230","position":5,"is_corresponding":false},{"id":784633,"name":"Donald C. Koroma","orcid":"0000-0001-7392-6371","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T23:52:51.201033Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}