The CA XII gene encodes Carbonic Anhydrase 12, a zinc metalloenzyme responsible for catalyzing the reversible hydration of carbon dioxide. The CA XII protein localizes in the basolateral membrane of ductal epithelia in the sweat gland and in the apical membrane in airway epithelia. By carrying out its function, the CA XII protein is believed to play a role in maintaining cellular pH and controlling salt transport.
Mutations in the gene have been linked to Isolated Hyperchlorhidrosis, a condition characterized by excessive sweat chloride levels, hyponatremic dehydration, hyperkalemia and a failure to thrive. A recent study has further suggested that along with the sweat glands, CA XII may also play a role in the function of the pulmonary airways.
The CA12 gene is located on the long arm of chromosome 15. It spans a length of 60.7 kb of DNA and its coding sequence is spread across 11 exons. It encodes a 39.4 kDa protein product consisting of 354 amino acids. An additional isoform of the CA12 protein, consisting of 343 amino acids, is encoded by an alternatively spliced transcript variant. The gene is found to be overexpressed in the colon, kidney, prostate, intestine and activated lymphocytes. The p.Glu143Lys substitution in the CA12 gene has been identified in several Bedouin families affected by Hyperchlorhidrosis.
Lee et al. (2016) described a consanguineous Omani family with two children affected by elevated sweat chloride, infantile FTT, recurrent hyponatremia and bilateral hyperkeratosis of the heels. Genetic analysis identified a novel homozygous c.363C>A mutation in exon 4 of the CA12 gene of both patients. It segregated in an autosomal recessive pattern in the family and was predicted to result in a p.His121Gln substitution. Studies of the mutation along with a previously reported p.Glu143Lys variant found that while they did not affect CA12 protein localization, they resulted in a near complete loss of enzyme activity at physiologic concentrations of extracellular chloride. CA12 deleterious variants were also identified in a 25-year-old Caucasian female with elevated sweat chloride and pulmonary airway disease. Hence, while spirometry and chest X-rays of the Omani proband were normal, it was suggested that bronchiectasis might be present but was undetected due to lack of CT-scan analysis. This study highlighted the importance of screening for CA12 mutations in individuals that have CF-like features in the sweat gland and lung but no CFTR mutations.