LRRC8C

LRRC8C
Identifiers
Aliases	LRRC8C , AD158, FAD158, leucine-rich repeat containing 8 family member C, leucine rich repeat containing 8 family member C, leucine rich repeat containing 8 VRAC subunit C
External IDs	OMIM: 612889; MGI: 2140839; HomoloGene: 12997; GeneCards: LRRC8C; OMA:LRRC8C - orthologs
Gene location (Human) Chr. Chromosome 1 (human) [1] Band 1p22.2 Start 89,633,072 bp [1] End 89,769,903 bp [1]
Gene location (Mouse) Chr. Chromosome 5 (mouse) [2] Band 5|5 E5 Start 105,667,254 bp [2] End 105,760,884 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm secondary oocyte cartilage tissue myocardium of left ventricle buccal mucosa cell white blood cell monocyte lower lobe of lung superficial temporal artery right ventricle Top expressed in left lung lobe carotid body ciliary body vestibular membrane of cochlear duct right lung lobe body of femur endothelial cell of lymphatic vessel Epithelium of choroid plexus mesenteric lymph nodes iris More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding volume-sensitive anion channel activity Cellular component cytoplasm integral component of membrane integral component of plasma membrane endoplasmic reticulum membrane membrane endoplasmic reticulum ion channel complex plasma membrane Biological process anion transmembrane transport ion transport fat cell differentiation regulation of anion transport signal transduction transmembrane transport transport cell volume homeostasis inorganic anion transport taurine transport aspartate transmembrane transport protein hexamerization cellular response to osmotic stress Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 84230 100604 Ensembl ENSG00000171488 ENSMUSG00000054720 UniProt Q8TDW0 Q8R502 RefSeq (mRNA) NM_032270 NM_133897 RefSeq (protein) NP_115646 NP_598658 Location (UCSC) Chr 1: 89.63 – 89.77 Mb Chr 5: 105.67 – 105.76 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Leucine-rich repeat-containing protein 8C is a protein that in humans is encoded by the LRRC8C gene. ^[5] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8D, and LRRC8E, is sometimes a subunit of the heteromer protein Volume-Regulated Anion Channel. ^[6] Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, ^[7] and that is not the only function these channels have been linked to.

While LRRC8C is one of many proteins that can be part of VRAC, research has found that it is not as crucial to the activity of the channel in comparison to LRRC8A and LRRC8D. ^{[8] [9] [10]} However, while we know that LRRC8A and LRRC8D are necessary for VRAC function, other studies have found that they are not sufficient for the full range of usual VRAC activity. ^[11] This is where the other LRRC8 proteins come in, such as LRRC8C, as the different composition of these subunits affects the range of specificity for VRACs. ^{[12] [10]}

In fact, a research study published in December 2024 seems to contradict the "non-crucial" role of LRRC8C and rather suggest multiple roles in different cell types. The study showed that two children bearing different, monoallelic variants in LRRC8C ^[13] had severe multi-organ congenital disease (TIMES syndrome; see OMIM https://omim.org/entry/621056). The genetic variants lead to constitutional activation of VRACs that become de-regulated and hyperactive.

In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5. ^[14]

References

1. GRCh38: Ensembl release 89: ENSG00000171488 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000054720 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: LRRC8A leucine rich repeat containing 8 family, member A".
6. Voss F, Ullrich F, Münch J (2014-05-09). "Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC" (PDF). Science (Submitted manuscript). 344 (6184): 634–8. Bibcode:2014Sci...344..634V. doi:10.1126/science.1252826. PMID   24790029. S2CID   24709412.
7. 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 (2): 293–3017. doi:10.1038/nrm.2016.29. ISSN   1471-0072. PMID   27033257. S2CID   40565653.^{[ permanent dead link ‍]}
8. Hyzinski-García MC, Rudkouskaya A, Mongin A (2014-11-15). "LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes". The Journal of Physiology. 592 (22): 4855–62. doi:10.1113/jphysiol.2014.278887. PMC   4259531 . PMID   25172945.
9. Yamada T, Wondergem R, Morrison R (2016-10-04). "Leucine-rich repeat containing protein LRRC8A is essential for swelling-activated Cl⁻ currents and embryonic development in zebrafish". Physiological Reports. 4 (19): e12940. doi:10.14814/phy2.12940. PMC   5064130 . PMID   27688432.
10. Planells-Cases R, Lutter D, Guyader C (2015-12-14). "Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs". EMBO Journal. 34 (24): 2993–3008. doi:10.15252/embj.201592409. PMC   4687416 . PMID   26530471.
11. Okada T, Islam MR, Tsiferova NA (2016-10-20). "Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR)". Channels. 11 (2): 109–120. doi:10.1080/19336950.2016.1247133. PMC   5398601 . PMID   27764579.
12. Lutter D, Ullrich F, Lueck JC (2017-03-15). "Selective transport of neurotransmitters and –modulators by distinct volume-regulated LRRC8 anion channels". Journal of Cell Science. 130 (6): 1122–1133. doi: 10.1242/jcs.196253 . PMID   28193731.
13. Quinodoz M, Rutz S, Peter V, Garavelli L, Innes AM, Lehmann EF, Kellenberger S, Peng Z, Barone A, Campos-Xavier B, Unger S, Rivolta C, Dutzler R, Superti-Furga A (2024). "De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder". The EMBO Journal. doi:10.1038/s44318-024-00322-y. PMC   11729881 . PMID   39623139.
14. Sawada A, Takihara Y, Kim JY (December 2003). "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans". Journal of Clinical Investigation. 112 (11): 1707–13. doi:10.1172/JCI18937. PMC   281644 . PMID   14660746.

Further reading

• Jentsch Thomas J (2016). "VRACs and other ion channels and transporters in the regulation of cell volume and beyond". Nature Reviews Molecular Cell Biology. 17 (2): 293–307. doi:10.1038/nrm.2016.29. PMID   27033257. S2CID   40565653.
• Eggermont D, Trouet I, Carton I, et al. (2001). "Cellular function and control of volume-regulated anion channels". Cell Biochemistry and Biophysics . 35 (3): 263–74. doi:10.1385/CBB:35:3:263. PMID   11894846. S2CID   31821726.
• Mongin Alexander (2016). "Volume-regulated anion channel – a frenemy within the brain". Pflügers Archiv. 468 (3): 421–441. doi:10.1007/s00424-015-1765-6. PMC   4752865 . PMID   26620797.
• Nagase T, Kikuno R, Ishikawa KI, et al. (2000). "Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro". DNA Res. 7 (1): 65–73. doi: 10.1093/dnares/7.1.65 . PMID   10718198.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• Clark HF, Gurney AL, Abaya E, et al. (2003). "The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC   403697 . PMID   12975309.
• Sawada A, Takihara Y, Kim JY, et al. (2004). "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans". J. Clin. Invest. 112 (11): 1707–13. doi:10.1172/JCI18937. PMC   281644 . PMID   14660746.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi: 10.1038/ng1285 . PMID   14702039.
• Kubota K, Kim JY, Sawada A, et al. (2004). "LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins". FEBS Lett. 564 (1–2): 147–52. doi:10.1016/S0014-5793(04)00332-1. PMID   15094057.
• Humphray SJ, Oliver K, Hunt AR, et al. (2004). "DNA sequence and analysis of human chromosome 9". Nature. 429 (6990): 369–74. Bibcode:2004Natur.429..369H. doi:10.1038/nature02465. PMC   2734081 . PMID   15164053.
• Smits G, Kajava AV (2004). "LRRC8 extracellular domain is composed of 17 leucine-rich repeats". Mol. Immunol. 41 (5): 561–2. doi:10.1016/j.molimm.2004.04.001. PMID   15183935.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC   528928 . PMID   15489334.
• Otsuki T, Ota T, Nishikawa T, et al. (2007). "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries". DNA Res. 12 (2): 117–26. doi: 10.1093/dnares/12.2.117 . PMID   16303743.
• Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi: 10.1016/j.cell.2006.09.026 . PMID   17081983. S2CID   7827573.