Alternative titles; symbols
HGNC Approved Gene Symbol: CA1
Cytogenetic location: 8q21.2 Genomic coordinates (GRCh38): 8:85,327,608-85,378,113 (from NCBI)
Carbonic anhydrases (CAs; carbonate dehydratase; carbonate hydrolyase; EC 4.2.1.1) form a large family of genes encoding zinc metalloenzymes of great physiologic importance. As catalysts of the reversible hydration of carbon dioxide, these enzymes participate in a variety of biologic processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid (Dodgson et al., 1991). CAs are encoded by members of 3 independent CA gene families, i.e., alpha-CA, beta-CA, and gamma-CA (Hewett-Emmett and Tashian, 1996). Genes in the alpha-carbonic anhydrase family encode either active carbonic anhydrase isozymes or 'acatalytic' (i.e., devoid of CO2 hydration activity) carbonic anhydrase-related proteins. Alpha-carbonic anhydrases show extensive diversity in tissue distribution and in their putative or established biologic functions. Some of the alpha-CAs are expressed in almost all tissues (e.g., CA II, 611492), whereas some show a more restricted expression (e.g., CA VI (114780) in salivary glands). In cells, they may reside in cytoplasm, in mitochondria, or in secretory granules, or associate with membranes.
Erythrocyte carbonic anhydrase has 2 isoenzymes with different amino acid sequences and specific activities. B and C were the original designations for these 2 major forms which later were called CA I (or A) and CA II (or B; 611492), respectively. Tashian (1969) reviewed the biochemical genetics of the 2 forms of red cell carbonic anhydrase, which are under the control of separate autosomal loci.
Andersson et al. (1972) stated that CA I is the major form of the enzyme in human red cells. They found that the protein consists of 260 amino acids. Barlow et al. (1987) cloned human carbonic anhydrase I cDNA.
CA I and CA II are linked in the rodent genus Cavia (Carter, 1972), closely linked in an Old World monkey, Macaca nemestrina (DeSimone et al., 1973), and tightly linked in the mouse (Eicher et al., 1976).
Using a cDNA clone of the CA1 gene in the study of human-rodent hybrids, Butterworth et al. (1985) and Edwards et al. (1986) assigned the CA1 gene to chromosome 8, which carries a cluster of CA genes.
By somatic cell genetic techniques and in situ hybridization, Davis et al. (1986, 1987) mapped the CA1 and CA3 (114750) genes to 8q13-q22. By pulsed field gel electrophoresis, Lowe et al. (1991) determined that the order of the genes is CA2, CA3, CA1. CA2 and CA3 are separated by 20 kb and are transcribed in the same direction, away from CA1. CA1 is separated from CA3 by over 80 kb and is transcribed in the opposite direction to CA2 and CA3. Lowe et al. (1991) concluded that the arrangement of the genes is consistent with proposals that the duplication event that gave rise to CA1 predated the duplication that gave rise to CA2 and CA3. The order of the 3 genes differs from that suggested for the mouse based on recombination frequency.
Tashian (1992) reviewed the gene organization and evolutionary relationships of the carbonic anhydrases. See also Hewett-Emmett and Tashian (1996).
Gao et al. (2007) performed proteomic analysis on vitreous fluid samples and found that the CA1 concentration from patients with diabetic retinopathy (see 603933) was 15.3 and 8.2 times higher than that from nondiabetic patients and diabetics with no diabetic retinopathy, respectively. Intravitreous injection of CA1 in rats increased retinal vessel leakage and caused intraretinal edema. CA1-induced alkalinization of vitreous increased kallilkrein (see 147910) and its generation of factor XIIa (see 610619); complement-1 inhibitor (C1NH; 606860), neutralizing antibody to prekallikrein (KLKB1; 229000), and bradykinin receptor (see 600337) antagonism decreased CA1-induced retinal edema. Subdural infusion of CA1 in rats induced cerebral vascular permeability. Gao et al. (2007) concluded that extracellular CA1 mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.
By starch gel electrophoresis, Tashian et al. (1963) detected a genetically determined variant of erythrocyte carbonic anhydrase.
The amino acid change in several CA I mutants was determined by Carter et al. (1972). Moore et al. (1973) demonstrated the autosomal dominant inheritance of CA I and CA II variants.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Carbonic Anhydrase I Deficiency
In a family on the Greek island of Icaria, Kendall and Tashian (1977) found virtually complete absence of erythrocyte carbonic anhydrase I in 3 persons and reduced levels thought to represent the heterozygous state in 2 others. No obvious hematologic or renal consequences were found in any of them. Venta et al. (1987) reported preliminary observations involving restriction analysis of DNA from white cells of CA I-deficient members of this family, which showed that the deficiency is not caused by a major deletion in at least 1 part of the gene. Wagner et al. (1991) and Tashian (1992) reported that CA I-deficient members of this family have a missense mutation in exon 7 of their CA1 gene (arg246-to-his; 114800.0002). Replacement of the highly conserved arg246 is the probable cause of the CA I deficiency.
Carbonic anhydrase Guam has substitution of arginine for glycine (Tashian and Carter, 1976). Omoto et al. (1981) established identity of a CA-1 variant in Philippine Negritos, CA-1(3N), to CA-1(Guam); both have substitution of arginine for glycine at amino acid 253.
In healthy members with almost complete absence of red cell CA I in the Icaria family reported by Kendall and Tashian (1977), Wagner et al. (1991) found an arg246-to-his missense mutation in the CA1 gene.
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Eicher, E. M., Stern, R. H., Womack, J. E., Davisson, M. T., Roderick, T. H., Reynolds, S. C. Evolution of mammalian carbonic anhydrase loci by tandem duplication: close linkage of Car-1 and Car-2 to the centromere region of chromosome 3 of the mouse. Biochem. Genet. 14: 651-660, 1976. [PubMed: 825106] [Full Text: https://doi.org/10.1007/BF00485843]
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Wagner, L. E., Venta, P. J., Tashian, R. E. A human carbonic anhydrase I deficiency appears to be caused by a destabilizing amino acid substitution (246arg-to-his). Isozyme Bull. 24: 35 only, 1991.