Abstract
Cataract, the loss of ocular lens transparency, accounts for ∼50% of worldwide blindness and has been associated with water and solute transport dysfunction across lens cellular barriers. We show that neutral amino acid antiporter LAT2 (Slc7a8) and uniporter TAT1 (Slc16a10) are expressed on mouse ciliary epithelium and LAT2 also in lens epithelium. Correspondingly, deletion of LAT2 induced a dramatic decrease in lens essential amino acid levels that was modulated by TAT1 defect. Interestingly, the absence of LAT2 led to increased incidence of cataract in mice, in particular in older females, and a synergistic effect was observed with simultaneous lack of TAT1. Screening SLC7A8 in patients diagnosed with congenital or age-related cataract yielded one homozygous single nucleotide deletion segregating in a family with congenital cataract. Expressed in HeLa cells, this LAT2 mutation did not support amino acid uptake. Heterozygous LAT2 variants were also found in patients with cataract some of which showed a reduced transport function when expressed in HeLa cells. Whether heterozygous LAT2 variants may contribute to the pathology of cataract needs to be further investigated. Overall, our results suggest that defects of amino acid transporter LAT2 are implicated in cataract formation, a situation that may be aggravated by TAT1 defects.
Highlights
Cataract, the condition of partial or complete loss of transparency in the ocular lens, is the most frequent cause for vision impairment worldwide (51%
A strong LAT2 signal localized to the basolateral side of the lens epithelium where it co-localized with the Na,K-ATPase (Figures 1I,K,L)
The expression of LAT2 or TAT1 on both sides of the ciliary epithelium and of LAT2 on the aqueous humor-facing basolateral side of the lens epithelium support the hypothesis that these transporters play an important role for the transport of amino acids from the blood to the lens and for lens amino acid homeostasis
Summary
The condition of partial or complete loss of transparency in the ocular lens, is the most frequent cause for vision impairment worldwide (51%). Early onset cataract, which is either present at birth or developing within the first few years of life, affects a minority of patients (∼3–6/10,000 births) (Graw, 2004; Shiels and Hejtmancik, 2013; Medsinge and Nischal, 2015). This latter type follows Mendelian inherited patterns where X-linked recessive, autosomal dominant and autosomal recessive modes of inheritance have been observed in about 30 different causative genes (Shiels and Hejtmancik, 2013).
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