Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration

Zhenglin Yang, Bernardo V. Alvarez, Christina Chakarova, Li Jiang, Goutam Karan, Jeanne M. Frederick, Yu Zhao, Yves Sauvé, Xi Li, Eberhart Zrenner, Bernd Wissinger, Anneke I. Den Hollander, Bradley Katz, Wolfgang Baehr, Frans P. Cremers,Joseph R. Casey, Shomi S. Bhattacharya, Kang Zhang

Human Molecular Genetics, Volume 14, Issue 2, 15 January 2005, Pages 255–265,


Retinitis pigmentosa (RP) is the most prevalent group of inherited retinal degeneration, affecting approximately 1 in 3500 persons or a total of 1.8 million people worldwide (1,2). Clinical features of RP include night blindness, constriction and progressive loss of peripheral visual field affecting rod photoreceptors, followed by eventual loss of central vision (cones). RP may be transmitted as an autosomal dominant, recessive or X-linked trait (3,4). All known RP genes are expressed either in photoreceptors or in retinal pigment epithelium (RPE), and are, to the most part, involved in photoreceptor structure, phototransduction, photoreceptor development, the retinoid cycle or RNA splicing.

Retinal phototransduction is modulated by pH changes in its surrounding environment (5). It has been demonstrated that the amplitude of rod photoreceptor responses will decrease by ∼70% when the extracellular pH was decreased to 6.0 (6). Furthermore, there will also be a concomitant decrease in the Na+ conductance of rod photoreceptor outer segments (7). Despite exquisite sensitivity to the extracellular pH changes, photoreceptors paradoxically have a high rate of metabolism (8) and consequently high rate of endogenous acid production. As by-products of energy production in photoreceptors, a large amount of carbon dioxide and bicarbonate is generated from oxidative phosphorylation in mitochondria in the inner segments and lactic acid is generated from the inner and outer segments (9). Additional acid is generated from H+ release from cGMP turnover in the outer segment (10), and H+ influx due to Ca++/H+ exchanger activity in the plasma membrane of inner segment (11). The increase in acid load and lowering of intracellular pH are prevented by its removal from retina and RPE and release to blood stream in the choriocapillaris in the choroid, which is located adjacent to RPE and photoreceptors.

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