Dysfunctional LAT2 Amino Acid Transporter Is Associated With Cataract in Mouse and Humans

Area of Science:

• Ophthalmology
• Molecular Biology
• Genetics

Background:

• Cataract causes approximately 50% of global blindness, often linked to impaired solute and water transport in the ocular lens.
• The neutral amino acid transporter LAT2 (Slc7a8) and the uniporter TAT1 (Slc16a10) are crucial for maintaining lens homeostasis.

Purpose of the Study:

• To investigate the role of LAT2 and TAT1 transporters in the development of cataract.
• To identify genetic variations in LAT2 associated with human cataract formation.

Main Methods:

• Utilized mouse models with targeted deletions of LAT2 and TAT1 genes.
• Analyzed amino acid levels in the ocular lens of knockout mice.
• Screened SLC7A8 gene in patients with congenital and age-related cataracts.
• Performed functional assays of mutated LAT2 variants in HeLa cells.

Main Results:

• Deletion of LAT2 significantly reduced essential amino acid levels in the lens, modulated by TAT1 deficiency.
• LAT2-deficient mice exhibited a higher incidence of cataract, particularly older females, with a synergistic effect when TAT1 was also absent.
• A homozygous SLC7A8 deletion in a family with congenital cataract resulted in a non-functional LAT2 transporter.
• Heterozygous LAT2 variants found in cataract patients showed reduced transport function in vitro.

Conclusions:

• Disruptions in the amino acid transporter LAT2 are implicated in cataract development.
• The absence or dysfunction of LAT2 can lead to decreased lens amino acid levels and increased cataract incidence.
• Concomitant defects in TAT1 may exacerbate cataract formation.
• Specific LAT2 mutations are linked to congenital cataract, and further research is needed on heterozygous variants.