Alternative titles; symbols
HGNC Approved Gene Symbol: CLCA1
Cytogenetic location: 1p22.3 Genomic coordinates (GRCh38) : 1:86,468,927-86,500,259 (from NCBI)
CLCA1 belongs to the calcium-dependent chloride channel family. Chloride channels are involved in the regulation of electrolytic fluxes and thereby modulate secretion, absorption, cell volume, and membrane potential (summary by Agnel et al. (1999)).
The murine calcium-activated chloride channel Clca1 (Gandhi et al., 1998), the bovine calcium-activated chloride channel Clca1, and bovine lung-endothelial cell adhesion molecule-1 (Lu-ECAM-1) are members of a family of proteins that appear to mediate a calcium-activated chloride conductance in a variety of tissues. These proteins share high degrees of homology in size, sequence (75 to 89% identity), and predicted structure, but differ significantly in their tissue distributions. By screening a human genomic library with the open reading frame of bovine Lu-ECAM-1, Gruber et al. (1998) cloned a human member of this family, CLCA1. Northern blot analysis detected a 3.3-kb CLCA1 transcript only in human small intestine and colon mucosa. In situ hybridization showed CLCA1 expression exclusively in intestinal basal crypt epithelium and goblet cells. Gruber et al. (1998) cloned a human small intestine CLCA1 cDNA using RT-PCR with primers based on the genomic sequence. The CLCA1 cDNA encodes a deduced 914-amino acid protein with a calculated molecular mass of 100.9 kD. Human CLCLA1 shares 67% amino acid identity with mouse Clca1, bovine Clca1, and bovine Lu-ECAM-1. The predicted human CLCLA1 protein has a signal sequence, 4 transmembrane domains, a large hydrophobic region at its C terminus, and a number of potential glycosylation and phosphorylation sites.
Based on glycosylation site scanning and protease protection assays of CLCA2 (604003), Gruber et al. (1999) predicted that CLCA1 contains 5 transmembrane domains.
Using bovine Cacc1 to query a human EST database, followed by RACE of a human colon cDNA library, Agnel et al. (1999) cloned CLCA1, which they called CACC1. The deduced 914-amino acid protein has an N-terminal signal peptide and a highly conserved HExxH zinc-binding motif. CACC1 shares 62% amino acid identity with CACC2 (CLCA4; 616857) and 45% identity with CACC3 (CLCA2; 604003). Northern blot analysis detected a 2.9-kb transcript that was highly expressed in colon and small intestine, with weaker expression in stomach and prostate. RNA dot blot analysis of 50 human tissues showed additional CACC1 expression in uterus, appendix, kidney, testis, and fetal spleen.
Gruber et al. (1998) demonstrated that recombinant human CLCA1 was expressed as a precursor protein that was processed into 2 cell surface-associated subunits. Expression of recombinant CLCA1 protein in HEK 293 cells resulted in an increase in whole-cell calcium-sensitive chloride currents that were outwardly rectified and inhibited by DIDS, dithiothreitol, and niflumic acid.
Using gene expression microarrays, Woodruff et al. (2007) found that CLCA1, periostin (POSTN; 608777), and SERPINB2 (PAI2; 173390) were upregulated in airway epithelial cells of individuals with asthma (see 600807), but not smokers. Corticosteroid treatment downregulated expression of these 3 genes and upregulated expression of FKBP51 (602623). High baseline expression of CLCA1, POSTN, and SERPINB2 was associated with a good clinical response to corticosteroids, whereas high expression of FKBP51 was associated with a poor response. Treatment of airway epithelial cells with IL13 resulted in increased expression of CLCA1, POSTN, and SERPINB2, an effect that could be suppressed by corticosteroids.
Gruber et al. (1998) determined that the CLCA1 gene contains 15 exons and spans 31.9 kb. An L1 transposable element is located within the predicted promoter region.
Gruber et al. (1998) mapped the CLCA1 gene to chromosome 1p31-p22 by FISH.
Pauli et al. (2000) reported that CLCA1 maps to a cluster of CLCA genes on chromosome 1p31-p22. The mouse Clca1 gene maps to a syntenic gene cluster on chromosome 3H2-H3.
Gross (2016) mapped the CLCA1 gene to chromosome 1p22.3 based on an alignment of the CLCA1 sequence (GenBank AF127036) with the genomic sequence (GRCh38).
Agnel, M., Vermat, T., Culouscou, J.-M. Identification of three novel members of the calcium-dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea. FEBS Lett. 455: 295-301, 1999. [PubMed: 10437792] [Full Text: https://doi.org/10.1016/s0014-5793(99)00891-1]
Gandhi, R., Elble, R. C., Gruber, A. D., Schreur, K. D., Ji, H.-L., Fuller, C. M., Pauli, B. U. Molecular and functional characterization of a calcium-sensitive chloride channel from mouse lung. J. Biol. Chem. 273: 32096-32101, 1998. [PubMed: 9822685] [Full Text: https://doi.org/10.1074/jbc.273.48.32096]
Gross, M. B. Personal Communication. Baltimore, Md. 3/11/2016.
Gruber, A. D., Elble, R. C., Ji, H.-L., Schreur, K. D., Fuller, C. M., Pauli, B. U. Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca(2+)-activated Cl- channel proteins. Genomics 54: 200-214, 1998. [PubMed: 9828122] [Full Text: https://doi.org/10.1006/geno.1998.5562]
Gruber, A. D., Schreur, K. D., Ji, H.-L., Fuller, C. M., Pauli, B. U. Molecular cloning and transmembrane structure of hCLCA2 from human lung, trachea, and mammary gland. Am. J. Physiol. 276: C1261-C1270, 1999. [PubMed: 10362588] [Full Text: https://doi.org/10.1152/ajpcell.1999.276.6.C1261]
Pauli, B. U., Abdel-Ghany, M., Cheng, H.-C., Gruber, A. D., Archibald, H. A., Elble, R. C. Molecular characteristics and functional diversity of CLCA family members. Clin. Exp. Pharm. Physiol. 27: 901-905, 2000. [PubMed: 11071307] [Full Text: https://doi.org/10.1046/j.1440-1681.2000.03358.x]
Woodruff, P. G., Boushey, H. A., Dolganov, G. M., Barker, C. S., Yang, Y. H., Donnelly, S., Ellwanger, A., Sidhu, S. S., Dao-Pick, T. P., Pantoja, C., Erle, D. J., Yamamoto, K. R., Fahy, J. V. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc. Nat. Acad. Sci. 104: 15858-15863, 2007. [PubMed: 17898169] [Full Text: https://doi.org/10.1073/pnas.0707413104]