Together with its β-subunit OSTM1, ClC-7 performs 2Cl/H exchange across lysosomal membranes. Pathogenic variants in either gene cause lysosome-related pathologies, including osteopetrosis and lysosomal storage. variants can cause recessive or dominant disease. Different variants entail different sets of symptoms. Loss of ClC-7 causes osteopetrosis and mostly neuronal lysosomal storage. A recently reported mutation (p.Tyr715Cys) causes widespread severe lysosome pathology (hypopigmentation, organomegaly, and delayed myelination and development, “HOD syndrome”), but no osteopetrosis. We now describe two additional HOD individuals with the previously described p.Tyr715Cys and a novel p.Lys285Thr mutation, respectively. Both mutations decreased ClC-7 inhibition by PI(3,5)P and affected residues lining its binding pocket, and shifted voltage-dependent gating to less positive potentials, an effect partially conferred to WT subunits in WT/mutant heteromers. This shift predicts augmented pH gradient-driven Cl uptake into vesicles. Overexpressing either mutant induced large lysosome-related vacuoles. This effect depended on Cl/H-exchange, as shown using mutants carrying uncoupling mutations. Fibroblasts from the p.Y715C patient also displayed giant vacuoles. This was not observed with p.K285T fibroblasts probably due to residual PI(3,5)P sensitivity. The gain of function caused by the shifted voltage-dependence of either mutant likely is the main pathogenic factor. Loss of PI(3,5)P inhibition will further increase current amplitudes, but may not be a general feature of HOD. Overactivity of ClC-7 induces pathologically enlarged vacuoles in many tissues, which is distinct from lysosomal storage observed with the loss of ClC-7 function. Osteopetrosis results from a loss of ClC-7, but osteoclasts remain resilient to increased ClC-7 activity.

中文翻译：

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CLCN7 的功能获得性变异导致色素沉着不足和溶酶体贮积病


ClC-7 与其 β 亚基 OSTM1 一起在溶酶体膜上进行 2Cl/H 交换。任一基因的致病变异都会导致溶酶体相关的病理，包括骨硬化症和溶酶体储存。变异可导致隐性或显性疾病。不同的变体会带来不同的症状。 ClC-7 的缺失会导致石骨症和大部分神经元溶酶体储存。最近报道的突变 (p.Tyr715Cys) 会导致广泛的严重溶酶体病理（色素沉着不足、器官肿大、髓鞘形成和发育延迟，“HOD 综合征”），但不会导致骨硬化症。我们现在描述了另外两个 HOD 个体，分别具有先前描述的 p.Tyr715Cys 和新的 p.Lys285Thr 突变。两种突变均降低了 PI(3,5)P 对 ClC-7 的抑制作用，并影响了其结合袋内的残基，并将电压依赖性门控转变为较弱的正电势，这种效应部分赋予了 WT/突变异聚体中的 WT 亚基。这种转变预示着 pH 梯度驱动的 Cl 对囊泡的吸收会增加。过表达任一突变体都会诱导大的溶酶体相关液泡。这种效应取决于 Cl/H 交换，如使用携带解偶联突变的突变体所示。 p.Y715C 患者的成纤维细胞也显示出巨大的液泡。 p.K285T 成纤维细胞没有观察到这一点，可能是由于残留的 PI(3,5)P 敏感性。由任一突变体的电压依赖性改变引起的功能获得可能是主要致病因素。 PI(3,5)P 抑制的丧失将进一步增加电流幅度，但可能不是 HOD 的一般特征。 ClC-7 的过度活性会在许多组织中诱导病理性扩大的液泡，这与 ClC-7 功能丧失时观察到的溶酶体储存不同。 骨石症是由 ClC-7 缺失引起的，但破骨细胞仍能抵抗 ClC-7 活性的增加。