Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.

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Abstract
The clinical, radiological and pathological findings in 3 siblings affected with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification were reported. In an effort to explain the pleiotropic effects of the mutation producing this disorder, a defect was postulated in carbonic anhydrase II (CA II), the only one of the 3 soluble isozymes of carbonic anhydrase that is known to be synthesized in kidney and brain. Biochemical and immunological evidence is reported for the virtual absence of CA II in erythrocytes of patients affected with this condition, whereas CA I level is not reduced. Levels of CA II in erythrocyte hemolysates from asymptomatic obligate heterozygotes are about half of normal. These findings: elucidate the basic defect in one form of inherited osteopetrosis; provide genetic evidence implicating CA II in osteoclast function and bone resorption; explain previous observations that carbonic anhydrase inhibitors block the normal parathyroid hormone-induced release of calcium from bone; clarify the role of renal Ca II in urinary acidification and bicarbonate reabsorption; and suggest a method to identify heterozygous carriers for the gene for this recessively inherited syndrome.