Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration.
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.
Yang
Zhenglin
Z
Department of Ophthalmology and Visual Science, University of Utah Health Science Center, Salt Lake City 84112, USA.
Alvarez
Bernardo V
BV
Chakarova
Christina
C
Jiang
Li
L
Karan
Goutam
G
Frederick
Jeanne M
JM
Zhao
Yu
Y
Sauvé
Yves
Y
Li
Xi
X
Zrenner
Eberhart
E
Wissinger
Bernd
B
Hollander
Anneke I Den
AI
Katz
Bradley
B
Baehr
Wolfgang
W
Cremers
Frans P
FP
Casey
Joseph R
JR
Bhattacharya
Shomi S
SS
Zhang
Kang
K
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
C498898:SLC4A4 protein, human; D027982:Sodium-Bicarbonate Symporters; D030741:Carbonic Anhydrase IV