Alternative titles; symbols
HGNC Approved Gene Symbol: CA12
SNOMEDCT: 709413001;
Cytogenetic location: 15q22.2 Genomic coordinates (GRCh38): 15:63,321,378-63,381,846 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q22.2 | Hyperchlorhidrosis, isolated | 143860 | Autosomal recessive | 3 |
The CA12 gene encodes carbonic anhydrase XII. Carbonic anhydrase (EC 4.2.1.1) is a zinc metalloenzymes that catalyzes the hydration of carbon dioxide to bicarbonate and protons. For background information on the CA family, see 114800.
Sahin et al. (1995) demonstrated that tumor immunogenicity in the autologous host is a common phenomenon and that the immunogenicity of human tumors is not due to the expression of a single antigen, but rather is conferred by multiple antigens. In 1 experiment, they screened a cDNA expression library derived from a renal cell carcinoma (RCC) with serum from the autologous patient. The authors isolated 7 clones, one of which represented a novel gene with similarity to the conserved regions and functional domains of carbonic anhydrases.
Tureci et al. (1998) cloned the gene identified by Sahin et al. (1995) from the RCC and named it CA XII. The cDNA sequence encodes a deduced 354-amino acid protein with a predicted molecular mass of 39,448 Da and features of a type I membrane protein. The extracellular CA domain shows 30 to 42% similarity with known human CAs, contains all 3 zinc-binding histidine residues found in active CAs, and contains 2 potential sites for asparagine glycosylation. Expression of the CA XII cDNA in mammalian cells produced a 43- to 44-kD doublet; treatment with PNGase (endoglycosidase) F resulted in a single 39-kD product. The recombinant CA XII had appreciable catalytic activity. By Northern blot analysis, the authors detected a 4.5-kb CA XII transcript in normal human kidney, colon, and activated lymphocytes. They found that CA XII is overexpressed in 10% of clear cell renal carcinomas, as compared with the corresponding normal renal tissue. Sequencing revealed no differences between the RCC-derived cDNA and a CA XII cDNA isolated from normal kidney.
Independently, Ivanov et al. (1998) identified and cloned a CA12 cDNA. The cDNA was found to contain a 1,062-bp ORF, a 115-bp 5-prime untranslated region (UTR), and a 1,591-bp 3-prime UTR. Compared to the CA12 cDNA isolated by Tureci et al. (1998), this cDNA contains 108 bp more in the 5-prime UTR. By use of a number of bioinformatics Web-based servers to analyze their cDNA and the deduced protein sequence, Ivanov et al. (1998) established the high degree of homology to members of the alpha-CA gene family. The deduced protein sequence was classified as a 1-pass transmembrane CA possessing an apparently intact catalytic domain in the extracellular CA module. Northern blot analysis showed that CA12 is highly expressed in colon, kidney, and prostate and moderately expressed in pancreas, ovary, and testis.
Liao et al. (2003) found that the transmembrane carbonic anhydrase IX (CA9; 603179) and carbonic anhydrase XII enzymes are expressed in the ciliary cells and, thus, may be involved in aqueous humor production. They suggested that CA12 may be a targeted gene in glaucoma.
Feldshtein et al. (2010) demonstrated that CA12 is expressed in the skin and plays a role in the electrolyte transport of sweat glands.
Lee et al. (2016) found expression of the CA12 gene in the basolateral compartment of reabsorptive ductal cells in human sweat glands. CA12 also showed apical localization in bronchiolar epithelia and was expressed in nasal epithelial cells. These findings suggested that CA12 may have alternative roles in both reabsorptive and secretory epithelial membranes.
By fluorescence in situ hybridization, Tureci et al. (1998) and Ivanov et al. (1998) assigned the CA12 gene to chromosome 15q22.
By sequencing of candidate genes within a region of homozygosity on chromosome 15q22, Feldshtein et al. (2010) identified a homozygous mutation in the CA12 gene (E143K; 603263.0001) in affected members of an Israeli Bedouin family with isolated hyperchlorhidrosis (HYCHL; 143860). The phenotype was relatively mild, and was characterized by visible salt precipitates after sweating, episodic hyponatremic dehydration, and poor feeding and slow weight gain in infancy. All affected individuals had normal growth and development after age 1 year. The mutation mildly reduced carbonic anhydrase activity, but caused a dramatic change in chloride-mediated negative feedback regulation of the enzyme, leading to excessive chloride secretion in sweat.
By genomewide linkage analysis followed by candidate gene sequencing in 3 consanguineous Bedouin families with salt wasting in sweat, Muhammad et al. (2011) identified homozygosity for the E143K mutation in the CA12 gene.
In 3 patients from 2 unrelated families with isolated hyperchlorhidrosis, in whom mutations in the CFTR gene (602421) were excluded, Lee et al. (2016) identified biallelic mutations in the CA12 gene (603263.0002-603263.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Studies of patient cells and in vitro functional expression studies were consistent with a loss-of-function effect.
In affected members of a consanguineous Israeli Bedouin kindred with autosomal recessive isolated hyperchlorhidrosis (HYCHL; 143860), Feldshtein et al. (2010) identified a homozygous 427G-A transition in exon 4 of the CA12 gene, resulting in a glu143-to-lys (E143K) substitution in a highly conserved region near the third zinc ligand domain. The mutant enzyme showed about 70% residual activity compared to wildtype and was highly inhibited by acetazolamide. However, the mutant protein was much more sensitive to inhibition by anions, including chloride, bromide, and iodide, compared to the wildtype protein. Thus, the mutation mildly reduced carbonic anhydrase activity, but caused a dramatic change in chloride-mediated negative feedback regulation of the enzyme, leading to excessive chloride secretion in sweat. Heterozygosity for the mutation was found in 1 of 300 Bedouin controls. The phenotype was relatively mild, and was characterized by visible salt precipitates after sweating, episodic hyponatremic dehydration, and poor feeding and slow weight gain in infancy. All affected individuals had normal growth and development after age 1 year.
By genomewide linkage analysis followed by candidate gene sequencing in 3 consanguineous Bedouin families with salt wasting in sweat, Muhammad et al. (2011) identified homozygosity for the E143K mutation. The substitution was predicted to disrupt the positioning of the second coordination shell, resulting in decreased protein-metal affinity and impaired catalytic activity. The heterozygous mutation was found in 3 of 192 Bedouin controls (frequency of 0.78%). The 3 families were from the same clan and were unrelated to the kindred reported by Feldshtein et al. (2010).
In a 25-year-old woman (family A) with autosomal recessive isolated hyperchlorhidrosis (HYCHL; 143860), Lee et al. (2016) identified compound heterozygous mutations in the CA12 gene: a G-to-A transition in intron 10 (c.908-1G-A, NM_001218.4), demonstrated to result in splicing abnormalities and aberrant RNA transcripts, and a 4-bp insertion (c.859_860insACCT; 603263.0003) in exon 8, predicted to result in a frameshift and premature termination. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The splice site mutation was found in heterozygous state in 53 individuals in the ExAC database, whereas the 4-bp insertion was not found in ExAC. Analysis of patient cells showed that the 4-bp insertion escaped nonsense-mediated mRNA decay because it occurred in the last exon of CA12, and resulted in premature termination. The splice site variant resulted in the production of aberrant transcripts. Expression of the mutations into HEK293 cells resulted in decreased levels of unglycosylated CA12 protein.
For discussion of the 4-bp insertion (c.859_860insACCT, NM_001218.4) in exon 8 of the CA12 gene that was found in compound heterozygous state in a patient with autosomal recessive isolated hyperchlorhidrosis (HYCHL; 143860) by Lee et al. (2016), see 603263.0002.
In 2 sibs, born of consanguineous Omani parents (family B), with autosomal recessive isolated hyperchlorhidrosis (HYCHL; 143860), Lee et al. (2016) identified a homozygous c.363C-A transversion (c.363C-A, NM_001218.4) in exon 4 of the CA12 gene, predicted to result in a his121-to-gln (H121Q) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the mutant protein was expressed and localized properly to the basolateral membrane, but enzymatic activity was reduced by 84 to 99% compared to wildtype, consistent with a loss of function.
Feldshtein, M., Elkrinawi, S., Yerushalmi, B., Marcus, B., Vullo, D., Romi, H., Ofir, R., Landau, D., Sivan, S., Supuran, C. T., Birk, O. S. Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII. Am. J. Hum. Genet. 87: 713-720, 2010. [PubMed: 21035102] [Full Text: https://doi.org/10.1016/j.ajhg.2010.10.008]
Ivanov, S. V., Kuzmin, I., Wei, M.-H., Pack, S., Geil, L., Johnson, B. E., Stanbridge, E. J., Lerman, M. I. Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc. Nat. Acad. Sci. 95: 12596-12601, 1998. [PubMed: 9770531] [Full Text: https://doi.org/10.1073/pnas.95.21.12596]
Lee, M., Vecchio-Pagan, B., Sharma, N., Waheed, A., Li, X., Raraigh, K. S., Robbins, S., Han, S. T., Franca, A. L., Pellicore, M. J., Evans, T. A., Arcara, K. M., Nguyen, H., Luan, S., Belchis, D., Hertecant, J., Zabner, J., Sly, W. S., Cutting, G. R. Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease. Hum. Molec. Genet. 25: 1923-1933, 2016. [PubMed: 26911677] [Full Text: https://doi.org/10.1093/hmg/ddw065]
Liao, S.-Y., Ivanov, S., Ivanova, A., Ghosh, S., Cote, M. A., Keefe, K., Coca-Prados, M., Stanbridge, E. J., Lerman, M. I. Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma. J. Med. Genet. 40: 257-262, 2003. [PubMed: 12676895] [Full Text: https://doi.org/10.1136/jmg.40.4.257]
Muhammad, E., Leventhal, N., Parvari, G., Hanukoglu, A., Hanukoglu, I., Chalifa-Caspi, V., Feinstein, Y., Weinbrand, J., Jacoby, H., Manor, E., Nagar, T., Beck, J. C., Sheffield, V. C., Hershkovitz, E., Parvari, R. Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of carbonic anhydrase 12. Hum. Genet. 129: 397-405, 2011. [PubMed: 21184099] [Full Text: https://doi.org/10.1007/s00439-010-0930-4]
Sahin, U., Tureci, O., Schmitt, H., Cochlovius, B., Johannes, T., Schmits, R., Stenner, F., Luo, G., Schobert, I., Pfreundschuh, M. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Nat. Acad. Sci. 92: 11810-11813, 1995. [PubMed: 8524854] [Full Text: https://doi.org/10.1073/pnas.92.25.11810]
Tureci, O., Sahin, U., Vollmar, E., Siemer, S., Gottert, E., Seitz, G., Parkkila, A. K., Shah, G. N., Grubb, J. H., Pfreundschuh, M., Sly, W. S. Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers. Proc. Nat. Acad. Sci. 95: 7608-7613, 1998. [PubMed: 9636197] [Full Text: https://doi.org/10.1073/pnas.95.13.7608]