Characterisation of SLC38A8 and Its Role in Retinal Pathways and Disease

ABSTRACT Background This study investigates the role of the SLC38A8 gene. SLC38A8 facilitates glutamine influx, which converts to glutamate in the visual pathway. Mutations in SLC38A8 are associated with FHONDA syndrome, a subtype of foveal hypoplasia with congenital nystagmus and optic‐nerve‐decussation defects without pigmentation leading to severe vision loss. Methods In vivo and in vitro methods were conducted using retinal cell lines overexpressing SLC38A8 , and Slc38a8 / Slc38a7 gene‐edited mice to evaluate visual function and physiological changes. Statistical analyses included two‐way ANOVA, multiple regression, and ANCOVA. Results In vitro, SLC38A8 overexpression influenced retinal gene expression, light detection, and visual perception, as well as glutamine and glutamate dynamics. In Y79 SNAT8‐OE cells, glutamate levels were significantly higher under light conditions compared to dark conditions at 12 h (3.4 ± 0.16 nmol/μl vs. 3.9 ± 0.17 nmol/μl, p = 0.0011) and 17 h (3.6 ± 0.22 nmol/μl vs. 4.5 ± 0.24 nmol/μl, p = 0.0001), a pattern not observed in control cells. SLC38A8 expression also increased significantly (RQ = 2.1 ± 0.11, p < 0.05) in Y79 cells under glutamine deprivation. In vivo, Slc38a8 ‐truncated gene mice exhibited altered testicular morphology, with significantly reduced volume (70.9 ± 5.1 mm 3 vs. 85.5 ± 6.7 mm 3 , p = 0.023), and reduced length (4.8 ± 0.2 mm vs. 5.4 ± 0.4 mm, p = 0.0169), alongside degenerative changes in germinal epithelium, and elevated liver enzyme. Despite normal eye morphology, retinal thickness, and visual evoked potentials, electroretinogram and behavioural tests indicated enhanced scotopic responsiveness with significant increases in a‐wave (162.98 ± 14.1 μv vs. 133.9 ± 36.9 μv, p = 1.5e‐07) and b‐wave amplitudes (274.82 ± 25.2 μv vs. 199.9 ± 56.1 μv, p = 3.02e‐09). Conclusions Our findings underscore SLC38A8 role in retinal function and glutamine‐glutamate metabolism, with clinical implications for FHONDA and potential future dietary intervention targeting glutamine or glutamate.