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

Abstract

The clinical, radiological, and pathological findings in three siblings affected with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification have been reported. In an effort to explain the pleiotropic effects of the mutation producing this disorder, we postulated a defect in carbonic anhydrase H (CA II), the only one of the three soluble isozymes of carbonic anhydrase that is.known to be synthesized in kidney and brain. We report here biochemical and immunological evidence 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: (i) elucidate the basic defect in one form of inherited osteopetrosis; (ii) provide genetic evidence implicating CA II in osteoclast function and bone resorption; (iii) explain previous observations that carbonic anhydrase inhibitors block the normal parathyroid hormone-induced release of calcium from bone; (iv) clarify the role of renal CA H in urinary acidification and bicarbonate reabsorption; and (v) suggest a method to identify heterozygous carriers for the gene for this recessively inherited syndrome.

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…CAII regulates cellular pH, CO 2 , and HCO 3 -transport, and maintains H 2 O and electrolyte balance by reversible hydration of CO 2 . CAII affects synaptic remodeling, consistent with the notion that a deficiency of CAII leads to cognitive defects varying from disabilities to severe mental retardation, suggesting the importance of CAII in cognitive function (351). Though levels of CAII are elevated, CAII activity is diminished in the AD brain (271), likely caused by the oxidative modification of the enzyme.…”

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

“…CA catalyzes CO 2 hydration and the reverse reaction between H ϩ and HCO 3 Ϫ ions, which helps in the maintenance of intracellular pH (66,67). CA II deficiency in humans is an autosomal recessive disease characterized by renal tubular acidosis, osteopetrosis, cerebral calcification, and growth retardation (68,69). However, previous studies reported that CA II promotes cardiomyocyte hypertrophy and its inhibition reverts hypertrophy (70,71).…”

Engraftment and survival following hematopoietic stem cell transplantation for osteopetrosis using a reduced intensity conditioning regimen

“…[3][4][5] Other involved genes include isolated reports of rare mutations in the gray lethal gene, 6 as well as abnormalities in the carbonic anhydrase II gene. 7 The deposition of bone by osteoblasts without resorption by osteoclasts results in marked increase in bone density and causes encroachment of bone marrow space resulting in progressive marrow failure and compensatory extramedullary hematopoiesis. 8,9 Compression of cranial nerves leads to neurological deficits, particularly blindness, that may occur early in life.…”