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. 1983 May;80(9):2752–2756. doi: 10.1073/pnas.80.9.2752

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

W S Sly, D Hewett-Emmett, M P Whyte, Y S Yu, R E Tashian
PMCID: PMC393906  PMID: 6405388

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 II (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 II in urinary acidification and bicarbonate reabsorption; and (v) suggest a method to identify heterozygous carriers for the gene for this recessively inherited syndrome.

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Selected References

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  1. Aarskog D., Asknes L., Haneberg B., Julshamn K. Acute response of parathyroid hormone in congenital osteopetrosis. Acta Paediatr Scand Suppl. 1979;277:75–80. doi: 10.1111/j.1651-2227.1979.tb06196.x. [DOI] [PubMed] [Google Scholar]
  2. Beighton P., Hamersma H., Cremin B. J. Osteopetrosis in South Africa. The benign, lethal and intermediate forms. S Afr Med J. 1979 Apr 21;55(17):659–665. [PubMed] [Google Scholar]
  3. Bourke E., Delaney V. B., Mosawi M., Reavey P., Weston M. Renal tubular acidosis and osteopetrosis in siblings. Nephron. 1981;28(6):268–272. doi: 10.1159/000182216. [DOI] [PubMed] [Google Scholar]
  4. Caniggia A., Gennari C., Lore F., Nuti R., Galli M. Effects of parathyroid hormone and calcitonin on plasma and nephrogenous cyclic adenosine-3',5'-monophosphate in normal subjects and in pathological conditions. Eur J Clin Invest. 1980 Apr;10(2 Pt 1):99–105. doi: 10.1111/j.1365-2362.1980.tb02067.x. [DOI] [PubMed] [Google Scholar]
  5. Carter N. D., Hewett-Emmett D., Jeffrey S., Tashian R. E. Testosterone-induced, sulfonamide-resistant carbonic anhydrase isozyme of rat liver is indistinguishable from skeletal muscle carbonic anhydrase III. FEBS Lett. 1981 Jun 1;128(1):114–118. doi: 10.1016/0014-5793(81)81094-0. [DOI] [PubMed] [Google Scholar]
  6. DULCE H. J., SIEGMUND P., KOERBER F., SCHUETTE E. [On the biochemistry of the dissolution of bone. 3. On the presence of carbonic anhydrase in bones]. Hoppe Seylers Z Physiol Chem. 1960 Aug 31;320:163–167. doi: 10.1515/bchm2.1960.320.1.163. [DOI] [PubMed] [Google Scholar]
  7. Dobyan D. C., Bulger R. E. Renal carbonic anhydrase. Am J Physiol. 1982 Oct;243(4):F311–F324. doi: 10.1152/ajprenal.1982.243.4.F311. [DOI] [PubMed] [Google Scholar]
  8. DuBose T. D., Jr, Pucacco L. R., Carter N. W. Determination of disequilibrium pH in the rat kidney in vivo: evidence of hydrogen secretion. Am J Physiol. 1981 Feb;240(2):F138–F146. doi: 10.1152/ajprenal.1981.240.2.F138. [DOI] [PubMed] [Google Scholar]
  9. DuBose T. D., Jr, Pucacco L. R., Seldin D. W., Carter N. W., Kokko J. P. Microelectrode determination of pH and PCO2 in rat proximal tubule after benzolamide: evidence for hydrogen ion secretion. Kidney Int. 1979 Jun;15(6):624–629. doi: 10.1038/ki.1979.82. [DOI] [PubMed] [Google Scholar]
  10. Gay C. V., Mueller W. J. Carbonic anhydrase and osteoclasts: localization by labeled inhibitor autoradiography. Science. 1974 Feb 1;183(4123):432–434. doi: 10.1126/science.183.4123.432. [DOI] [PubMed] [Google Scholar]
  11. Guibaud P., Larbre F., Freycon M. T., Genoud J. Ostéopétrose et acidose rénale tubulaire. Deux cas de cette association dans une fratrie. Arch Fr Pediatr. 1972 Mar;29(3):269–286. [PubMed] [Google Scholar]
  12. Hopkinson D. A., Coppock J. S., Mühlemann M. F., Edwards Y. H. The detection and differentiation of the products of the human carbonic anhydrase loci, CAI and CAII using fluorogenic substrates. Ann Hum Genet. 1974 Oct;38(2):155–162. doi: 10.1111/j.1469-1809.1974.tb01946.x. [DOI] [PubMed] [Google Scholar]
  13. Johnston C. C., Jr, Lavy N., Lord T., Vellios F., Merritt A. D., Deiss W. P., Jr Osteopetrosis. A clinical, genetic, metabolic, and morphologic study of the dominantly inherited, benign form. Medicine (Baltimore) 1968 Mar;47(2):149–167. [PubMed] [Google Scholar]
  14. Kendall A. G., Tashian R. E. Erythrocyte carbonic anhydrase I: inherited deficiency in humans. Science. 1977 Jul 29;197(4302):471–472. doi: 10.1126/science.406674. [DOI] [PubMed] [Google Scholar]
  15. Koester M. K., Pullan L. M., Noltmann E. A. The p-nitrophenyl phosphatase activity of muscle carbonic anhydrase. Arch Biochem Biophys. 1981 Oct 15;211(2):632–642. doi: 10.1016/0003-9861(81)90499-9. [DOI] [PubMed] [Google Scholar]
  16. Kondo T., Taniguchi N., Taniguchi K., Matsuda I., Murao M. Inactive form of erythrocyte carbonic anhydrase B in patients with primary renal tubular acidosis. J Clin Invest. 1978 Sep;62(3):610–617. doi: 10.1172/JCI109167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kumpulainen T., Nyström S. H. Immunohistochemical localization of carbonic anhydrase isoenzyme C in human brain. Brain Res. 1981 Sep 7;220(1):220–225. doi: 10.1016/0006-8993(81)90230-4. [DOI] [PubMed] [Google Scholar]
  18. Lees M. B., Sapirstein V. S., Reiss D. S., Kolodny E. H. Carbonic anhydrase and 2',3' cyclic nucleotide 3'-phosphohydrolase activity in normal human brain and in demyelinating diseases. Neurology. 1980 Jul;30(7 Pt 1):719–725. doi: 10.1212/wnl.30.7.719. [DOI] [PubMed] [Google Scholar]
  19. Lucci M. S., Pucacco L. R., DuBose T. D., Jr, Kokko J. P., Carter N. W. Direct evaluation of acidification by rat proximal tubule: role of carbonic anhydrase. Am J Physiol. 1980 May;238(5):F372–F379. doi: 10.1152/ajprenal.1980.238.5.F372. [DOI] [PubMed] [Google Scholar]
  20. Maren T. H. Carbonic anhydrase: chemistry, physiology, and inhibition. Physiol Rev. 1967 Oct;47(4):595–781. doi: 10.1152/physrev.1967.47.4.595. [DOI] [PubMed] [Google Scholar]
  21. Maren T. H., Rayburn C. S., Liddell N. E. Inhibition by anions of human red cell carbonic anhydrase B: physiological and biochemical implications. Science. 1976 Feb 6;191(4226):469–472. doi: 10.1126/science.813299. [DOI] [PubMed] [Google Scholar]
  22. Marks S. C., Jr Morphological evidence of reduced bone resorption in osteopetrotic (op) mice. Am J Anat. 1982 Feb;163(2):157–167. doi: 10.1002/aja.1001630205. [DOI] [PubMed] [Google Scholar]
  23. McKinley D. N., Whitney P. L. Particulate carbonic anhydrase in homogenates of human kidney. Biochim Biophys Acta. 1976 Oct 11;445(3):780–790. doi: 10.1016/0005-2744(76)90128-5. [DOI] [PubMed] [Google Scholar]
  24. Minkin C., Jennings J. M. Carbonic anhydrase and bone remodeling: sulfonamide inhibition of bone resorption in organ culture. Science. 1972 Jun 2;176(4038):1031–1033. doi: 10.1126/science.176.4038.1031. [DOI] [PubMed] [Google Scholar]
  25. Ohlsson A., Stark G., Sakati N. Marble brain disease: recessive osteopetrosis, renal tubular acidosis and cerebral calcification in three Saudi Arabian families. Dev Med Child Neurol. 1980 Feb;22(1):72–84. doi: 10.1111/j.1469-8749.1980.tb04307.x. [DOI] [PubMed] [Google Scholar]
  26. Osborne W. R., Tashian R. E. An improved method for the purification of carbonic anhydrase isozymes by affinity chromatography. Anal Biochem. 1975 Mar;64(1):297–303. doi: 10.1016/0003-2697(75)90434-0. [DOI] [PubMed] [Google Scholar]
  27. Pocker Y., Sarkanen S. Carbonic anhydrase: structure catalytic versatility, and inhibition. Adv Enzymol Relat Areas Mol Biol. 1978;47:149–274. doi: 10.1002/9780470122921.ch3. [DOI] [PubMed] [Google Scholar]
  28. Sanyal G., Maren T. H. Thermodynamics of carbonic anhydrase catalysis. A comparison between human isoenzymes B and C. J Biol Chem. 1981 Jan 25;256(2):608–612. [PubMed] [Google Scholar]
  29. Sanyal G., Pessah N. I., Maren T. H. Kinetics and inhibition of membrane-bound carbonic anhydrase from canine renal cortex. Biochim Biophys Acta. 1981 Jan 15;657(1):128–137. doi: 10.1016/0005-2744(81)90136-4. [DOI] [PubMed] [Google Scholar]
  30. Sanyal G., Swenson E. R., Pessah N. I., Maren T. H. The carbon dioxide hydration activity of skeletal muscle carbonic anhydrase. Inhibition by sulfonamides and anions. Mol Pharmacol. 1982 Jul;22(1):211–220. [PubMed] [Google Scholar]
  31. Shapira E., Ben-Yoseph Y., Eyal F. G., Russell A. Enzymatically inactive red cell carbonic anhydrase B in a family with renal tubular acidosis. J Clin Invest. 1974 Jan;53(1):59–63. doi: 10.1172/JCI107559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Spicer S. S., Sens M. A., Tashian R. E. Immunocytochemical demonstration of carbonic anhydrase in human epithelial cells. J Histochem Cytochem. 1982 Sep;30(9):864–873. doi: 10.1177/30.9.6813372. [DOI] [PubMed] [Google Scholar]
  33. Tinker J. P., Coulson R., Weiner I. M. Dextran-bound inhibitors of carbonic anhydrase. J Pharmacol Exp Ther. 1981 Sep;218(3):600–607. [PubMed] [Google Scholar]
  34. Vainsel M., Fondu P., Cadranel S., Rocmans C., Gepts W. Osteopetrosis associated with proximal and distal tubular acidosis. Acta Paediatr Scand. 1972 Jul;61(4):429–434. doi: 10.1111/j.1651-2227.1972.tb15859.x. [DOI] [PubMed] [Google Scholar]
  35. Vogh B. P. The relation of choroid plexus carbonic anhydrase activity to cerebrospinal fluid formation: study of three inhibitors in cat with extrapolation to man. J Pharmacol Exp Ther. 1980 May;213(2):321–331. [PubMed] [Google Scholar]
  36. Waite L. C. Carbonic anhydrase inhibitors, parathyroid hormone and calcium metabolism. Endocrinology. 1972 Nov;91(5):1160–1165. doi: 10.1210/endo-91-5-1160. [DOI] [PubMed] [Google Scholar]
  37. Waite L. C., Volkert W. A., Kenny A. D. Inhibition of bone resorption by acetazolamide in the rat. Endocrinology. 1970 Dec;87(6):1129–1139. doi: 10.1210/endo-87-6-1129. [DOI] [PubMed] [Google Scholar]
  38. Whitney P. L., Briggle T. V. Membrane-associated carbonic anhydrase purified from bovine lung. J Biol Chem. 1982 Oct 25;257(20):12056–12059. [PubMed] [Google Scholar]
  39. Whyte M. P., Murphy W. A., Fallon M. D., Sly W. S., Teitelbaum S. L., McAlister W. H., Avioli L. V. Osteopetrosis, renal tubular acidosis and basal ganglia calcification in three sisters. Am J Med. 1980 Jul;69(1):64–74. doi: 10.1016/0002-9343(80)90501-x. [DOI] [PubMed] [Google Scholar]
  40. Wistrand P. J. Human renal cytoplasmic carbonic anhydrase. Tissue levels and kinetic properties under near physiological conditions. Acta Physiol Scand. 1980 Jul;109(3):239–248. doi: 10.1111/j.1748-1716.1980.tb06593.x. [DOI] [PubMed] [Google Scholar]
  41. Wistrand P. J. The importance of carbonic anhydrase B and C for the unloading of CO2 by the human erythrocyte. Acta Physiol Scand. 1981 Dec;113(4):417–426. doi: 10.1111/j.1748-1716.1981.tb06918.x. [DOI] [PubMed] [Google Scholar]

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