The Value of Inherited Deficiencies of Human Carbonic Anhydrase Isozymes in Understanding Their Cellular Roles^a

Abstract

Very little light has been shed on the role of the low-activity CA I isozyme in humans by studies on CA I-deficient individuals. On the other hand, CA II-deficient individuals exhibit abnormalities of bone, kidney and brain, implicating a functional role for the high-activity CA II isozyme in cells from these tissues and organs. It also appears that the CA II-deficient red cell is capable of normal respiratory function under unstressed conditions. In addition, there is some preliminary evidence that those organs such as the eye which primarily contain the CA II isozyme, may be able to function effectively in the absence of CA II.

Positive Renal Response to Intravenous Acetazolamide in Patients with Carbonic Anhydrase II Deficiency

“…This activity was attributed to the CA I isozyme, which is not diminished in these patients (22). These studies suggest that the CA 11-deficient erythrocytes are not functionally impaired in C02 transport in vivo.…”

“…We have since extended this finding to many other similarly affected families (22,30). The renal abnormalities in this syndrome are still incompletely understood.…”

“…A proximal component was suggested by HC03-wasting at normal plasma concentrations (i.e. a low Tm for HC03-) (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). A distal defect, profound in some patients, was evident from their inadequate ability to acidify their urine, even while quite acidotic…”

Localization of carbonic anhydrase IV in a specific capillary bed of the human eye.

“…Clinical observations in CA I-and CA II-deficient patients have been extremely helpful in delineating the respective physiological roles of these two isozymes (24,37,38). On the basis of this experience, identification of patients with CA IV deficiency and description of the ocular abnormalities of CA IV-deficient patients seem worthwhile goals.…”

Molecular analysis of G+C-rich upstream sequences regulating transcription of the human carbonic anhydrase II gene.

“…The carbonic anhydrase (CA) isozyme system is well suited for such an analysis, as it has been extensively studied at both the biochemical and molecular level (6,9). The wide distribution of the CA II isozyme lends itself to particularly interesting aspects of differential gene control, as CA II is found in almost all mammalian tissues, but it is differentially expressed in the cells of these tissues (7). The nucleotide sequences of the 5' regions of the CA II genes of humans and mice show a high degree of homology from 200 bases 5' of -550 G+C content and nine CCGCCC or GGGCGG boxes) and highly regulated genes (TATA box, P-globin-like tandem repeats, and limited cell-type expression) in the human CA II gene presents the possibility that this is an intermediate-type promoter (2) and may display unique regulatory mechanisms.…”