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Michael Romero, Heather Holmes, Uttio Roy Chowdhury, Cheryl Hann, Min-Hwang Chang, Michael Fautsch, An-Ping Chen; Ocular Indications of Partial Penetrance in Mice Heterozygous for NBCe1 (Slc4a4). Invest. Ophthalmol. Vis. Sci. 2013;54(15):5646.
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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. Although heterozygous carriers (parents and siblings) make some amount of the mutant form of NBCe1 protein, they have been considered asymptomatic. In 2007 a nbce1-knockout (NUL) mouse was reported; yet, analysis of these mice did not include ocular parameters. Our study sought to investigate the impact of nbce1-knockout (NUL) and heterozygosity (HET, +/-) on the eye.
Breeding pairs of HET-nbce1 mice were obtained from Dr. Gary Shull (U Cinc., OH) to generate NUL, HET and wild-type (WT) mice. Intraocular pressure (IOP) in non-anaesthetized mice (2 wk - 12 mo) was measured using a handheld rebound Tonometer (iCare). IOP was repeated in 5-6 animals (n) per genotype, R and L eye, while keeping time of day constant; “N” is the total number of IOP points. Since NUL’s die by 18d, we sacrificed and performed histological studies before 18 d. We also examined ocular histology of mice >10 mo.
IOP measurements indicate that young (2wk-3mo) WT (14.5 ± 1.3 mmHg; N=53) and HET (14.9 ± 1.1 mmHg; N=64) mice are similar (mean ±SD). IOP’s for NUL’s were erratic, but histology revealed NUL’s had no anterior chamber (AC), indicating a more severe phenotype than humans with recessive NBCe1 mutations. Ocular histology of young HETs was similar to young WTs. A second IOP-series in older mice (10-12 mo) showed that HETs had developed elevated IOP: WT (15.5 ± 1.1, N=118) and HET (19.7 ± 2.0, N=104). Histologically, older WTs and HETs had normal AC and angles. Surprisingly, the HET retinas were missing several layers: outer plexiform layer (OPL), outer nuclear layer (ONL) and rods. Significant cellular debris was present between the inner nuclear layer and the retinal pigmented epithelium (RPE).
Allelic variations in the NBCe1 gene may be a contributor to age-related onset of elevated IOP with concurrent retinal degeneration.
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