Bestrophin-2 is involved in the generation of intraocular pressure

PURPOSE. The bestrophin family of proteins has been demonstrated to generate or regulate Ca2+-activated Cl- conductances. Mutations in bestrophin-1 (Best1) cause several blinding eye diseases, but little is known about other bestrophin family members. This study involved disruption of the Best2 gene in mice. METHODS. The mouse Best2 gene was disrupted by replacing exons 1, 2, and part of exon 3 with a Lac Z. The expression profile of Bestrophin-2 ( Best2) was examined using RT-PCR, X-gal staining, and immunohistochemistry. Intraocular pressure ( IOP) was measured by anterior chamber cannulation. RESULTS. RT-PCR of mouse tissues revealed Best2 mRNA in eye, colon, nasal epithelia, trachea, brain, lung, and kidney. X-gal staining, confirmed expression in colon epithelia and in the eye, in the nonpigmented epithelia ( NPE). Best2 was not expressed in RPE cells. Best2 protein was observed only in NPE and colon epithelia. The absence of Best2 had no obvious deleterious effect on the mice. However, the Best2(-/-) mice were found to have significantly ( P < 0.02) diminished IOP with respect to the Best2(+/+) and Best2(+/-) littermates. The Best2(-/-) and Best2(+/-) mice responded better to the carbonic anhydrase inhibitor brinzolamide than did their Best2(+/+) littermates, although the beta-blocker timolol brought IOP to the same level, regardless of genotype. CONCLUSIONS. Best2 plays a role in the generation of IOP by regulating formation of aqueous humor, and inhibition of Best2 function represents an attractive new avenue for regulating IOP in individuals with glaucoma.