| Study | Key finding / discovery | Experimental approach | Significance |
|---|---|---|---|
| Zhang et al., 2023 | The ClC-7 ortholog maintains lysosomal luminal Cl- required for cathepsin B/L activity; loss of transporter function reduces chloride without abolishing acidification, causing defective cargo degradation and lysosomal membrane rupture. (pqac-00000008, pqac-00000009) | C. elegans genetics; loss-of-function mutants of clh-6/ClC-7 ortholog; lysosomal membrane damage reporters; chloride and pH measurements; cathepsin activity assays; in vitro chloride supplementation experiments. (pqac-00000008, pqac-00000009) | Shifted the field from viewing ClC-7 mainly as a support for acidification to recognizing luminal chloride itself as a direct regulator of lysosomal hydrolase function and membrane integrity. (pqac-00000008, pqac-00000009) |
| Wu/Freeman et al., 2023 | ClC-7 establishes a roughly 2- to 4-fold luminal chloride gradient in lysosomes/phagolysosomes and is required for efficient degradation and phagolysosome resolution even when acidification remains largely intact. (pqac-00000009) | Macrophage/phagolysosome functional studies summarized in JCB spotlight; ClC-7 knockout analysis; phagosomal degradation assays; chloride-sensitive measurements; assessment of phagolysosome maturation/resolution. (pqac-00000009) | Strengthened evidence that ClC-7 has a primary chloride-homeostasis role in degradative organelles, with relevance to innate immunity and phagocytic clearance. (pqac-00000009) |
| Polovitskaya et al., 2024 | Gain-of-function CLCN7 variants including Y715C and K285T cause HOD syndrome with hypopigmentation, organomegaly, delayed myelination/development, and lysosomal storage; the variants reduce PI(3,5)P2-mediated inhibition and shift voltage dependence to favor excess transport. (pqac-00000002, pqac-00000007) | Human genetics in affected patients; targeted sequencing; whole-cell patch clamp of plasma-membrane-targeted human ClC-7 mutants; lysosomal morphology studies in overexpression systems and patient fibroblasts. (pqac-00000002, pqac-00000007) | Demonstrated that not only loss-of-function but also transporter overactivity is pathogenic, defining a distinct CLCN7 disease mechanism separate from classical osteopetrosis. (pqac-00000002, pqac-00000007) |
| Hilton et al., 2025 | PI(3,5)P2 directly inhibits ClC-7 by binding at the transmembrane-cytosolic interface and remodeling transporter structure; disease-causing mutations disrupt this inhibitory network and increase transport activity. (pqac-00000012) | Functional electrophysiology, cryo-EM structural analysis, and molecular dynamics/computational modeling of ClC-7/Ostm1 and interface mutants. (pqac-00000012) | Provided a structural mechanism linking lysosomal phosphoinositide signaling to ClC-7 slow gating, lysosomal pH regulation, and gain-of-function disease. (pqac-00000012) |
| Chen et al., 2026 | Review synthesis identifies ClC-7 as one of the best-established ion transport systems in osteoclasts, acting with V-ATPase at the ruffled border and lysosomal system to support bone resorption and osteoclast function. (pqac-00000006) | Narrative review integrating osteoclast ion-channel/transporter literature, localization data, substrate/function assignments, and disease links. (pqac-00000006) | Useful translational summary placing CLCN7 in the broader osteoclast ion-transport network and highlighting its importance as a disease mechanism and potential therapeutic target in bone disorders. (pqac-00000006) |


*Table: This table summarizes major CLCN7/ClC-7 advances from 2023-2025, emphasizing new mechanistic insights into lysosomal chloride homeostasis, disease-causing gain-of-function variants, and structural regulation by PI(3,5)P2. It is useful for quickly linking each study to its methods and biological significance.*