Structure of the carbonic anhydrase VI (CA6) gene: evidence for two distinct groups within the alpha-CA gene family

The secreted carbonic anhydrase (CA VI) is believed to be one of the oldest mammalian CAs in evolutionary terms. To elucidate its gene structure and c ompare it with other members of the alpha-CA family, we cloned genomic frag ments encoding the bovine CA6 gene and determined its exon/intron organizat ion. The gene spans approx. 25 kb and consists of eight exons and seven int rons. Exon 1 encodes the 5' untranslated region, the signal peptide and the N-terminus of the mature enzyme, Exon 8 encodes the 3' untranslated region and the C-terminal extension that is unique to CA VI. Exons 2-7 encode the CA domain, which shows significant sequence similarity to other CAs. Two d istinct groups exist in the alpha-CA family on the basis of a comparison of the known gene structures. One group consists of the cytoplasmic (CA I, TI , III and VII) and mitochondrial (CA VI) members. The other group consists of the membrane-bound (CA IV and IX) and secreted (CA VI) members. In parti cular, the seven exon/intron boundaries in the CA domain of the CA6 gene ar e conserved in the CA9 gene, which encodes the multidomain protein CA IX th at is overexpressed in tumours and has transforming potential.