Leucine-rich repeat-containing protein 8C is a protein encoded by the human LRRC8Cgene.[5]
Function
LRRC8C is one of five LRRC8 proteins—along with LRRC8A, LRRC8B, LRRC8D, and LRRC8E—that can form subunits of the heteromeric volume-regulated anion channel (VRAC).[6] These channels play a vital role in cell volume regulation by transporting chloride ions and organic osmolytes—including taurine and glutamate—across the plasma membrane.[7]
Although LRRC8C can contribute to VRAC composition, it appears to be less essential for VRAC activity than core subunits LRRC8A and LRRC8D.[8][9][10] However, studies have shown that LRRC8A and LRRC8D alone are not sufficient to support the full functional diversity of VRACs.[11] The presence of additional LRRC8 subunits, including LRRC8C, modulates substrate selectivity and functional properties of VRACs.[12][10]
Clinical signficance
Recent findings suggest that LRRC8C may have more critical roles than previously recognized. A 2024 study identified monoallelic de novo variants in LRRC8C in two children with a severe congenital multisystem disorder (TIMES syndrome; see OMIM: https://omim.org/entry/621056).[13] These variants led to constitutive VRAC activation, resulting in channel hyperactivity and dysregulated ion transport, highlighting a pathogenic mechanism involving LRRC8C dysfunction.
Beyond its role in VRACs, the LRRC8 protein family has also been linked to agammaglobulinemia-5, a primary immunodeficiency disorder.[14]
^Jentsch TJ (2016-05-17). "VRACs and other ion channels and transporters in the regulation of cell volume and beyond". Nature Reviews. Molecular Cell Biology. 17 (5): 293–307. doi:10.1038/nrm.2016.29. ISSN1471-0072. PMID27033257. S2CID40565653.
Jentsch Thomas J (May 2016). "VRACs and other ion channels and transporters in the regulation of cell volume and beyond". Nature Reviews. Molecular Cell Biology. 17 (5): 293–307. doi:10.1038/nrm.2016.29. PMID27033257. S2CID40565653.
Eggermont J, Trouet D, Carton I, Nilius B (2001). "Cellular function and control of volume-regulated anion channels". Cell Biochemistry and Biophysics. 35 (3): 263–274. doi:10.1385/CBB:35:3:263. PMID11894846. S2CID31821726.
Kubota K, Kim JY, Sawada A, Tokimasa S, Fujisaki H, Matsuda-Hashii Y, et al. (Apr 2004). "LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins". FEBS Letters. 564 (1–2): 147–152. Bibcode:2004FEBSL.564..147K. doi:10.1016/S0014-5793(04)00332-1. PMID15094057.
Smits G, Kajava AV (Jul 2004). "LRRC8 extracellular domain is composed of 17 leucine-rich repeats". Molecular Immunology. 41 (5): 561–562. doi:10.1016/j.molimm.2004.04.001. PMID15183935.
