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)
End	89,769,903 bp
Gene location (Mouse)
Chr.	Chromosome 5 (mouse)
End	105,760,884 bp
RNA expression pattern
	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
	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
	84230
	100604
	ENSG00000171488
	ENSMUSG00000054720
	Q8TDW0
	Q8R502
	NM_032270
	NM_133897
	NP_115646
	NP_598658
	Wikidata
View/Edit Human	View/Edit Mouse

Leucine-rich repeat-containing protein 8C is a protein encoded by the human LRRC8C gene.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.⁸⁹¹⁰ 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.¹²¹⁰

Clinical significance

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

References

GRCh38: Ensembl release 89: ENSG00000171488 – Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000054720 – Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Entrez Gene: LRRC8A leucine rich repeat containing 8 family, member A".
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). New York, N.Y.: 634–638. Bibcode:2014Sci...344..634V. doi:10.1126/science.1252826. PMID 24790029. S2CID 24709412.
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. ISSN 1471-0072. PMID 27033257. S2CID 40565653.
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): 4855–4862. doi:10.1113/jphysiol.2014.278887. PMC 4259531. PMID 25172945.
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.
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". The EMBO Journal. 34 (24): 2993–3008. doi:10.15252/embj.201592409. PMC 4687416. PMID 26530471.
Okada T, Islam M, Tsiferova N (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). Austin, Tex.: 109–120. doi:10.1080/19336950.2016.1247133. PMC 5398601. PMID 27764579.
Lutter D, Ullrich F, Lueck J (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.
Quinodoz M, Rutz S, Peter V, Garavelli L, Innes AM, Lehmann EF, et al. (2024). "De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder". The EMBO Journal. 44 (2): 413–436. doi:10.1038/s44318-024-00322-y. PMC 11729881. PMID 39623139.
Sawada A, Takihara Y, Kim J (December 2003). "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans". The Journal of Clinical Investigation. 112 (11): 1707–1713. doi:10.1172/JCI18937. PMC 281644. PMID 14660746.

Further reading

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. PMID 27033257. S2CID 40565653.
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. PMID 11894846. S2CID 31821726.
Alexander M (Mar 2016). "Volume-regulated anion channel – a frenemy within the brain". Pflügers Archiv: European Journal of Physiology. 468 (3): 421–441. doi:10.1007/s00424-015-1765-6. PMC 4752865. PMID 26620797.
Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O (Feb 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 Research. 7 (1): 65–73. doi:10.1093/dnares/7.1.65. PMID 10718198.
Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S, Fujisaki H, et al. (Dec 2003). "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans". The Journal of Clinical Investigation. 112 (11): 1707–1713. doi:10.1172/JCI18937. PMC 281644. PMID 14660746.
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. PMID 15094057.
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. PMID 15183935.
Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, 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 Research. 12 (2): 117–126. doi:10.1093/dnares/12.2.117. PMID 16303743.
Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. (Nov 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–648. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000171488 – Ensembl, May 2017

[refGRCm38Ensembl-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.

[entrez-5] "Entrez Gene: LRRC8A leucine rich repeat containing 8 family, member A".

[Voss_2014-6] 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). New York, N.Y.: 634–638. Bibcode:2014Sci...344..634V. doi:10.1126/science.1252826. PMID 24790029. S2CID 24709412.

[Jentsch_2016-7] 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 (5): 293–307. doi:10.1038/nrm.2016.29. ISSN 1471-0072. PMID 27033257. S2CID 40565653.

[HyzinskiGarcia_2014-8] 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): 4855–4862. doi:10.1113/jphysiol.2014.278887. PMC 4259531. PMID 25172945.

[Yamada_2016-9] 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.

[Planells-Cases_2015-10] 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". The EMBO Journal. 34 (24): 2993–3008. doi:10.15252/embj.201592409. PMC 4687416. PMID 26530471.

[Okada_2016-11] Okada T, Islam M, Tsiferova N (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). Austin, Tex.: 109–120. doi:10.1080/19336950.2016.1247133. PMC 5398601. PMID 27764579.

[Lutter_2017-12] Lutter D, Ullrich F, Lueck J (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, et al. (2024). "De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder". The EMBO Journal. 44 (2): 413–436. doi:10.1038/s44318-024-00322-y. PMC 11729881. PMID 39623139.

[Sawada_2003-14] Sawada A, Takihara Y, Kim J (December 2003). "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans". The Journal of Clinical Investigation. 112 (11): 1707–1713. doi:10.1172/JCI18937. PMC 281644. PMID 14660746.

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