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Human Molecular Genetics Advance Access originally published online on November 24, 2004
Human Molecular Genetics 2005 14(2):255-265; doi:10.1093/hmg/ddi023
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Human Molecular Genetics, Vol. 14, No. 2 © Oxford University Press 2005; all rights reserved

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

Zhenglin Yang1,2,{dagger}, Bernardo V. Alvarez5,{dagger}, Christina Chakarova6,{dagger}, Li Jiang1,2, Goutam Karan1,2, Jeanne M. Frederick1, Yu Zhao1,2, Yves Sauvé1, Xi Li1,2, Eberhart Zrenner7, Bernd Wissinger7, Anneke I. Den Hollander8, Bradley Katz1, Wolfgang Baehr1,3,4, Frans P. Cremers8, Joseph R. Casey5, Shomi S. Bhattacharya6 and Kang Zhang1,2,4,*

1Department of Ophthalmology and Visual Science, University of Utah Health Science Center, Salt Lake City, UT 84112, USA, 2Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics and 3Department of Biology and 4Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA, 5CIHR Group in Molecular Biology of Membrane Proteins, Department of Physiology, University of Alberta, Edmonton, Canada T6G 2H7 and 6Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EV, UK, 7Universitätsaugenklinik Tübingen, Abt. Pathophysiologie des Sehens und Neuroophthalmologie, Tübingen, Germany and 8Department of Human Genetics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands

* To whom correspondence should be addressed. Tel: +1 8015856797; Fax: +1 8015853501; Email: kzhang{at}hmbg.utah.edu

Received September 16, 2004; Revised October 19, 2004; Accepted November 10, 2004

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.

{dagger} The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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