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

Hum Mol Genet. 2005 Jan 15;14(2):255-65. doi: 10.1093/hmg/ddi023.

Zhenglin Yang ¹, 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

Affiliations

Affiliation

1 Department of Ophthalmology and Visual Science, University of Utah Health Science Center, Salt Lake City 84112, USA.

PMID: 15563508 DOI: 10.1093/hmg/ddi023

Abstract

Retina and retinal pigment epithelium (RPE) belong to the metabolically most active tissues in the human body. Efficient removal of acid load from retina and RPE is a critical function mediated by the choriocapillaris. However, the mechanism by which pH homeostasis is maintained is largely unknown. Here, we show that a functional complex of Carbonic Anhydrase 4 (CA4) and Na+/bicarbonate co-transporter 1 (NBC1) is specifically expressed in the choriocapillaris and that missense mutations in CA4 linked to autosomal dominant rod-cone dystrophy disrupt NBC1-mediated HCO3- transport. Our results identify a novel pathogenic pathway in which a defect in a functional complex involved in maintaining pH balances, but not expressed in retina or RPE, leads to photoreceptor degeneration. The importance of a functional CA4 for survival of photoreceptors implies that CA inhibitors, which are widely used as medications, particularly in the treatment of glaucoma, may have long-term adverse effects on vision.

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