Alternative titles; symbols
HGNC Approved Gene Symbol: CLNS1A
Cytogenetic location: 11q14.1 Genomic coordinates (GRCh38): 11:77,614,530-77,637,794 (from NCBI)
Anguita et al. (1995) cloned a novel gene encoding the chloride channel I(Cln) from a human ocular ciliary epithelial cell cDNA library. The gene encodes a 237-amino acid polypeptide that is over 90% identical to rat and canine I(Cln). The predicted protein contains 4 putative transmembrane domains. By Northern blot analysis, Nagl et al. (1996) found that the gene is expressed as an approximately 1.7-kb message in a variety of human tissues.
Buyse et al. (1996) independently cloned I(Cln) from a leukemic cell line cDNA library and leukocyte RNA. Although I(Cln) has a predicted molecular mass of 26.2 kD, I(Cln) protein extracted from human endothelial cell lines migrated at 40 kD on SDS-PAGE. Buyse et al. (1996) suggested that anomalous migration was due to the high number of acidic amino acids in I(Cln), which has a pI of 3.8.
Schwartz et al. (1997) cloned I(Cln) from human reticulocyte cDNA. I(Cln) protein from red blood cell ghost membranes migrated as 2 bands, 37 and 43 kD, on SDS-PAGE. Schwartz et al. (1997) immunolocalized I(Cln) to the red blood cell membrane and, by the yeast 2-hybrid system, demonstrated that it formed stable complexes with beta-actin (102630). The authors suggested that I(Cln) is involved in chloride transport and volume regulation in red blood cells.
Guderian et al. (2011) stated that ICLN functions as a substrate adaptor in a trimeric complex with catalytic PRMT5 (604045) and MEP50 (WDR77; 611734) for arginine dimethylation of spliceosomal Sm proteins. By immunohistochemical analysis and cell fractionation, they found that ICLN predominantly localized with the PRMT5 complex in HeLa cell nuclei. RIOK1 (617753) also interacted with the PRMT5 complex, but in the cytoplasm in the absence of ICLN. In vitro competition assays revealed that ICLN and RIOK1 competed with each other for the same binding site on PRMT5. Guderian et al. (2011) concluded that ICLN and RIOK1 are adaptor proteins that recruit specific substrate proteins to the PRMT5 methyltransferase complex.
Dossena et al. (2011) found that overexpression of human ZNF706 (619526), which they called HSPC038, or ICLN increased the swelling-induced chloride current (ICl-swell) in HEK293 Phoenix cells. In contrast, knockdown of HSPC038 impaired ICl-swell in HEK293 Phoenix cells. Analysis with purified recombinant proteins revealed that ICLN and HSPC038 interacted directly. Fluorescence resonance energy transfer (FRET) experiments in principal collecting duct M1 cells showed that hypotonic shock induced HSPC038 translocation toward the cell membrane in spatial proximity to ICLN and significantly increased interaction between the proteins. With increased interaction with ICLN, HSPC038 improved translocation of ICLN to the cell membrane but did not modify expression of endogenous ICLN. Drug-induced interaction of HSPC038 with ICLN also upregulated ICl-swell. By nuclear magnetic resonance (NMR) analysis, the authors identified putative interacting sites for the ICLN/HSPC038 complex.
Using FRET analysis, Tamma et al. (2011) showed that treatment with epidermal growth factor (EGF; 131530) caused direct interaction between ICLN and HSPC038 and significantly enhanced their direct interaction with the plasma membrane in transfected NIH-3T3 mouse cells. Electrophysiologic studies revealed that EGF stimulation led to activation of a chloride current of modest magnitude resembling ICl-swell in NIH-3T3 cells in isotonic conditions. In contrast, EGF markedly upregulated ICl-swell in both naive and ICLN-overexpressing NIH-3T3 cells. The results indicated that EGF likely exerted its role in the modulation of volume-sensitive chloride currents through redistribution of ICLN and HSPC038 to the plasma membrane.
Nagl et al. (1996) cloned the genomic DNA of the CLNS1A gene and showed that the gene comprises several exons spanning 19 kb of the genome.
Nagl et al. (1996) used fluorescence in situ hybridization to localize the I(Cln) gene to chromosome 11q13.5-q14.1. Schwartz et al. (1997) mapped the I(Cln) gene to 11q13 by fluorescence in situ hybridization, and confirmed this map position by finding homologous sequence contained within a Human Gene Map marker from that region.
Pseudogene
By PCR strategies, Nagl et al. (1996) mapped an intronless copy of the CLNS1A gene, which they termed CLNS1B, to chromosome 6q13. Nagl et al. (1996) stated that further testing would reveal whether CLNS1B is a pseudogene or is functionally expressed.
Anguita, J., Chalfant, M. L., Civan, M. M., Coca-Prados, M. Molecular cloning of the human volume-sensitive chloride conductance regulatory protein, pI(Cln), from ocular ciliary epithelium. Biochem. Biophys. Res. Commun. 208: 89-95, 1995. [PubMed: 7887970] [Full Text: https://doi.org/10.1006/bbrc.1995.1309]
Buyse, G., De Greef, C., Raeymaekers, L., Droogmans, G., Nilius, B., Eggermont, J. The ubiquitously expressed pI(Cln) protein forms homomeric complexes in vitro. Biochem. Biophys. Res. Commun. 218: 822-827, 1996. [PubMed: 8579598] [Full Text: https://doi.org/10.1006/bbrc.1996.0146]
Dossena, S., Gandini, R., Tamma, G., Vezzoli, V., Nofziger, C., Tamplenizza, M., Salvioni, E., Bernardinelli, E., Meyer, G., Valenti, G., Wolf-Watz, M., Furst, J., Paulmichl, M. The molecular and functional interaction between ICln and HSPC038 proteins modulates the regulation of cell volume. J. Biol. Chem. 286: 40659-40670, 2011. [PubMed: 21917931] [Full Text: https://doi.org/10.1074/jbc.M111.260430]
Guderian, G., Peter, C., Wiesner, J., Sickmann, A., Schulze-Osthoff, K., Fischer, U., Grimmler, M. RioK1, a new interactor of protein arginine methyltransferase 5 (PRMT5), competes with pICln for binding and modulates PRMT5 complex composition and substrate specificity. J. Biol. Chem. 286: 1976-1986, 2011. [PubMed: 21081503] [Full Text: https://doi.org/10.1074/jbc.M110.148486]
Nagl, U. O., Erdel, M., Schmarda, A., Seri, M., Pinggera, G. M., Gschwentner, M., Duba, C., Galietta, L. J. V., Deetjen, P., Utermann, G., Paulmichl, M. Chromosomal localization of the genes (CLNS1A and CLNS1B) coding for the swelling-dependent chloride channel I(Cln). Genomics 38: 438-441, 1996. [PubMed: 8975725] [Full Text: https://doi.org/10.1006/geno.1996.0651]
Schwartz, R. S., Rybicki, A. C., Nagel, R. L. Molecular cloning and expression of a chloride channel-associated protein pI(Cln) in human young red blood cells: association with actin. Biochem. J. 327: 609-616, 1997. [PubMed: 9359436] [Full Text: https://doi.org/10.1042/bj3270609]
Tamma, G., Dossena, S., Nofziger, C., Valenti, G., Svelto, M., Paulmichl, M. EGF stimulates ICl-swell by a redistribution of proteins involved in cell volume regulation. Cell. Physiol. Biochem. 28: 1191-1202, 2011. [PubMed: 22179007] [Full Text: https://doi.org/10.1159/000335851]