Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. 1983 May; 80(9): 2752–2756.
PMCID: PMC393906

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


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.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Johnston CC, Jr, Lavy N, Lord T, Vellios F, Merritt AD, Deiss WP., Jr Osteopetrosis. A clinical, genetic, metabolic, and morphologic study of the dominantly inherited, benign form. Medicine (Baltimore) 1968 Mar;47(2):149–167. [PubMed]
  • Beighton P, Hamersma H, Cremin BJ. Osteopetrosis in South Africa. The benign, lethal and intermediate forms. S Afr Med J. 1979 Apr 21;55(17):659–665. [PubMed]
  • Marks SC., Jr Morphological evidence of reduced bone resorption in osteopetrotic (op) mice. Am J Anat. 1982 Feb;163(2):157–167. [PubMed]
  • Guibaud P, Larbre F, Freycon MT, 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]
  • 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. [PubMed]
  • Whyte MP, Murphy WA, Fallon MD, Sly WS, Teitelbaum SL, McAlister WH, Avioli LV. Osteopetrosis, renal tubular acidosis and basal ganglia calcification in three sisters. Am J Med. 1980 Jul;69(1):64–74. [PubMed]
  • 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. [PubMed]
  • Maren TH. Carbonic anhydrase: chemistry, physiology, and inhibition. Physiol Rev. 1967 Oct;47(4):595–781. [PubMed]
  • Pocker Y, Sarkanen S. Carbonic anhydrase: structure catalytic versatility, and inhibition. Adv Enzymol Relat Areas Mol Biol. 1978;47:149–274. [PubMed]
  • Waite LC, Volkert WA, Kenny AD. Inhibition of bone resorption by acetazolamide in the rat. Endocrinology. 1970 Dec;87(6):1129–1139. [PubMed]
  • Waite LC. Carbonic anhydrase inhibitors, parathyroid hormone and calcium metabolism. Endocrinology. 1972 Nov;91(5):1160–1165. [PubMed]
  • Minkin C, Jennings JM. Carbonic anhydrase and bone remodeling: sulfonamide inhibition of bone resorption in organ culture. Science. 1972 Jun 2;176(4038):1031–1033. [PubMed]
  • Kumpulainen T, Nyström SH. Immunohistochemical localization of carbonic anhydrase isoenzyme C in human brain. Brain Res. 1981 Sep 7;220(1):220–225. [PubMed]
  • Vogh BP. 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]
  • Wistrand PJ. Human renal cytoplasmic carbonic anhydrase. Tissue levels and kinetic properties under near physiological conditions. Acta Physiol Scand. 1980 Jul;109(3):239–248. [PubMed]
  • Dobyan DC, Bulger RE. Renal carbonic anhydrase. Am J Physiol. 1982 Oct;243(4):F311–F324. [PubMed]
  • Kendall AG, Tashian RE. Erythrocyte carbonic anhydrase I: inherited deficiency in humans. Science. 1977 Jul 29;197(4302):471–472. [PubMed]
  • Hopkinson DA, Coppock JS, Mühlemann MF, Edwards YH. 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. [PubMed]
  • Carter ND, Hewett-Emmett D, Jeffrey S, Tashian RE. 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. [PubMed]
  • Osborne WR, Tashian RE. An improved method for the purification of carbonic anhydrase isozymes by affinity chromatography. Anal Biochem. 1975 Mar;64(1):297–303. [PubMed]
  • Whitney PL, Briggle TV. Membrane-associated carbonic anhydrase purified from bovine lung. J Biol Chem. 1982 Oct 25;257(20):12056–12059. [PubMed]
  • Sanyal G, Pessah NI, Maren TH. Kinetics and inhibition of membrane-bound carbonic anhydrase from canine renal cortex. Biochim Biophys Acta. 1981 Jan 15;657(1):128–137. [PubMed]
  • McKinley DN, Whitney PL. Particulate carbonic anhydrase in homogenates of human kidney. Biochim Biophys Acta. 1976 Oct 11;445(3):780–790. [PubMed]
  • Koester MK, Pullan LM, Noltmann EA. The p-nitrophenyl phosphatase activity of muscle carbonic anhydrase. Arch Biochem Biophys. 1981 Oct 15;211(2):632–642. [PubMed]
  • Sanyal G, Swenson ER, Pessah NI, Maren TH. The carbon dioxide hydration activity of skeletal muscle carbonic anhydrase. Inhibition by sulfonamides and anions. Mol Pharmacol. 1982 Jul;22(1):211–220. [PubMed]
  • Sanyal G, Maren TH. Thermodynamics of carbonic anhydrase catalysis. A comparison between human isoenzymes B and C. J Biol Chem. 1981 Jan 25;256(2):608–612. [PubMed]
  • Wistrand PJ. 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. [PubMed]
  • Aarskog D, Asknes L, Haneberg B, Julshamn K. Acute response of parathyroid hormone in congenital osteopetrosis. Acta Paediatr Scand Suppl. 1979;277:75–80. [PubMed]
  • 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. [PubMed]
  • Gay CV, Mueller WJ. Carbonic anhydrase and osteoclasts: localization by labeled inhibitor autoradiography. Science. 1974 Feb 1;183(4123):432–434. [PubMed]
  • DULCE HJ, 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. [PubMed]
  • DuBose TD, Jr, Pucacco LR, Carter NW. Determination of disequilibrium pH in the rat kidney in vivo: evidence of hydrogen secretion. Am J Physiol. 1981 Feb;240(2):F138–F146. [PubMed]
  • Lucci MS, Pucacco LR, DuBose TD, Jr, Kokko JP, Carter NW. Direct evaluation of acidification by rat proximal tubule: role of carbonic anhydrase. Am J Physiol. 1980 May;238(5):F372–F379. [PubMed]
  • DuBose TD, Jr, Pucacco LR, Seldin DW, Carter NW, Kokko JP. 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. [PubMed]
  • Tinker JP, Coulson R, Weiner IM. Dextran-bound inhibitors of carbonic anhydrase. J Pharmacol Exp Ther. 1981 Sep;218(3):600–607. [PubMed]
  • Bourke E, Delaney VB, Mosawi M, Reavey P, Weston M. Renal tubular acidosis and osteopetrosis in siblings. Nephron. 1981;28(6):268–272. [PubMed]
  • Spicer SS, Sens MA, Tashian RE. Immunocytochemical demonstration of carbonic anhydrase in human epithelial cells. J Histochem Cytochem. 1982 Sep;30(9):864–873. [PubMed]
  • Shapira E, Ben-Yoseph Y, Eyal FG, 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. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Lees MB, Sapirstein VS, Reiss DS, Kolodny EH. 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. [PubMed]
  • Maren TH, Rayburn CS, Liddell NE. Inhibition by anions of human red cell carbonic anhydrase B: physiological and biochemical implications. Science. 1976 Feb 6;191(4226):469–472. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • OMIM
    OMIM record citing PubMed
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...