title: Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration.
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.
authors.affiliation: Department of Ophthalmology and Visual Science, University of Utah Health Science Center, Salt Lake City 84112, USA.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.forename: Bernardo V
authors.initials: BV
authors.lastname: Alvarez
authors.forename: Christina
authors.initials: C
authors.lastname: Chakarova
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Goutam
authors.initials: G
authors.lastname: Karan
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Frederick
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yves
authors.initials: Y
authors.lastname: Sauvé
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Anneke I Den
authors.initials: AI
authors.lastname: Hollander
authors.forename: Bradley
authors.initials: B
authors.lastname: Katz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Frans P
authors.initials: FP
authors.lastname: Cremers
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casey
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
mesh_terms: D030741:Carbonic Anhydrase IV / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D009154:Mutation; D010375:Pedigree; D010786:Photoreceptor Cells / Q000378:metabolism*; D027982:Sodium-Bicarbonate Symporters / Q000378:metabolism
chemical_list: C498898:SLC4A4 protein, human; D027982:Sodium-Bicarbonate Symporters; D030741:Carbonic Anhydrase IV