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Human Molecular Genetics Advance Access published online on November 24, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi023
© 2004 by Oxford University Press
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Article

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

Zhenglin Yang 1, Bernardo V. Alvarez 2, Christina Chakarova 3, Li Jiang 1, Goutam Karan 1, Jeanne M. Frederick 4, Yu Zhao 1, Yves Sauvé 4, Xi Li 1, Eberhart Zrenner 5, Bernd Wissinger 5, Anneke I. Den Hollander 6, Bradley Katz 4, Wolfgang Baehr 7, Frans P. Cremers 6, Joseph R. Casey 2, Shomi S. Bhattacharya 3, and Kang Zhang 8*

1 Department of Ophthalmology and Visual Science, University of Utah Health Science Center, Salt Lake City, UT 84112, USA; Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84132, USA
2 Department of Physiology, CIHR Group in Molecular Biology of Membrane Proteins, University of Alberta, Edmonton, Canada T6G 2H7
3 Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EV, UK
4 Department of Ophthalmology and Visual Science, University of Utah Health Science Center, Salt Lake City, UT 84112, USA
5 Universitätsaugenklinik Tübingen, Abt. Pathophysiologie des Sehens und Neuroophthalmologie, Tübingen, Germany
6 Department of Human Genetics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
7 Department of Ophthalmology and Visual Science, University of Utah Health Science Center, Salt Lake City, UT 84112, USA; Departments of Biology, University of Utah, Salt Lake City, UT 84112, USA; Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA
8 Department of Ophthalmology and Visual Science, University of Utah Health Science Center, Salt Lake City, UT 84112, USA; Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84132, USA; Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA

* To whom correspondence should be addressed.
Kang Zhang, E-mail: kzhang{at}hmbg.utah.edu


  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 carbonic anhydrase 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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