LRRC8C

Last updated

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
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 encoded by the human LRRC8C gene. [5]

Contents

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]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000171488 Ensembl, May 2017
  2. 1 2 3 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). New York, N.Y.: 634–638. 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 (5): 293–307. doi:10.1038/nrm.2016.29. ISSN   1471-0072. PMID   27033257. S2CID   40565653.
  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.
  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. 1 2 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.
  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.
  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.
  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.

Further reading