De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder

ABSTRACT: Volume-regulated anion channels (VRACs) are multimeric proteins composed of different paralogs of the LRRC8 family. They are activated in response to hypotonic swelling, but little is known about their specific functions. We studied two human individuals with the same congenital syndrome affecting blood vessels, brain, eyes, and bones. The LRRC8C gene harbored de novo variants in both patients, located in a region of the gene encoding the boundary between the pore and a cytoplasmic domain, which is depleted of sequence variations in control subjects. When studied by cryo-EM, both LRRC8C mutant proteins assembled as their wild-type counterparts, but showed increased flexibility, suggesting a destabilization of subunit interactions. When co-expressed with the obligatory LRRC8A subunit, the m

SUBMITTER: Dr. Mathieu Quinodoz 

PROVIDER: S-SCDT-10_1038-S44318-024-00322-Y | biostudies-other |

REPOSITORIES: biostudies-other