Clcn6-flox Mouse

Clcn6, encoding the ClC-6 Cl⁻/H⁺ -exchanger, is a member of the CLC family of voltage-gated chloride channels. It is involved in the endosomal-lysosomal pathway, where it functions as an electric shunt for proton pumping and in luminal Cl⁻ accumulation, playing a crucial role in maintaining endolysosomal ion homeostasis [3].

Knock-out of Clcn6 on the Dahl Salt-Sensitive (SS) rat background led to lower diastolic blood pressure, suggesting its role in blood pressure regulation. The loss of Clcn6 also affected the mRNA expression of nearby genes like Mthfr, Nppa, and Nppb in the AGTRAP-PLOD1 locus [2]. In a mouse model of a patient-derived Clcn6 variant (p.E200A), severe neurodegeneration with features of neuronal ceroid lipofuscinoses (NCLs) was observed. Mutant ClC-6E200A blocked autophagic flux, activated transcription factors EB (TFEB) and E3 (TFE3), and increased lysosomal biogenesis by suppressing mTORC1-TFEB signaling [1].

In conclusion, Clcn6 is essential for maintaining endolysosomal ion homeostasis and is involved in blood pressure regulation and autophagic-lysosomal function. Mouse models, such as the Clcn6 knockout and knock-in models, have been instrumental in revealing its role in neurodegenerative diseases like NCLs and in blood pressure-related physiological processes [1,2].