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Michael F Romero, Heather L Holmes, Uttio Roy Chowdhury, Cheryl R Hann, Minhwang Chang, Michael P Fautsch, An-Ping Chen; Mutants in NBCe1A isoform have elevated Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2415.
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Recessive human mutations in the electrogenic Na+ bicarbonate cotransporter (NBCe1, Slc4a4) cause severe proximal renal tubular acidosis (pRTA) as well as bilateral glaucoma and cataracts. Previously we reported that heterozygosity of the entire nbce1 gene (nbce1(+/-); HET) resulted in elevated intraocular pressure (IOP) by 1 year of age. In this study, we have analyzed an NBCe1A isoform specific knockout mouse (nbce1A(-/-)) to better establish a relationship between elevated IOP and retina-optic nerve damage.
Using TALEN-technology, we specifically disrupted the NBCe1A isoform (nbce1A(-/-)) to mimic a mutation (Q29x) found in a NBCe1 patient who has proximal renal tubular acidosis and elevated IOP glaucoma, but no evidence of cataracts or other eye pathologies. IOP of homozygous knockouts, HETs and wild-type littermate control mice were measured using a handheld rebound Tonometer (iCare). Blood and urine chemistries were measured using a pHOx Ultra analyzer (Nova).
TALEN-targeting of the NBCe1A isoform resulted in 14 distinct nbce1A genotypes including 3 frame-shift deletion knockouts. We have begun to characterize this new (KOA) line compared to nbce1A(+/-))(HetA) and nbce1A(+/+) (WtA). KOA (nbce1A(-/-)) animals live longer than whole gene nbce1(-/-) mice (>100 v 18 days) and also show significantly elevated IOP (KOA =16.0±0.2; HetA =14.6±0.2; WtA =14.6±0.2 mmHg; multiple measures on 4-8 mice/group). nbce1A(-/-) mice are acidotic (i.e., low pH and [HCO3-]):
Mutations in the NBCe1A isoform show elevated IOP along with acidosis. We are developing a new model of elevated IOP glaucoma in mice, by examining allelic variations in the NBCe1 gene and the NBCe1A isoform. These new animals will allow testing to determine if NBCe1A is contributor to age-related onset of elevated IOP and the ensuing optical neuropathies.
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