A slc38a8 mouse model of FHONDA syndrome faithfully recapitulates the visual deficits of albinism without pigmentation defects

Abstract

SummaryPurposeWe aimed to generate and phenotype a mouse model of FHONDA (Foveal Hypoplasia, Optic Nerve Decussation Defects, and Anterior Segment Dysgenesis), a rare disease associated with mutations inSLC38A8that causes severe visual alterations similar to albinism without affecting pigmentation.MethodsThe FHONDA mouse model was generated with CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 technology using an RNA guide targeting theScl38a8murine locus. The resulting mice were backcrossed to C57BL/6J. Melanin content was measured using spectrophotometry. Retinal cell architecture was analyzed through light and electron microscopy. Retinal projections to the brain were evaluated with anterograde labelling in embryos and adults. Visual function was assessed by electroretinography (ERG) and the optomotor test (OT).ResultsFrom numerousSlc38a8mouse mutant alleles generated, we selected one that encodes a truncated protein (p.196Pro*, equivalent to p.199Pro* in the human protein) closely resembling a mutant allele described in patients (p.200Gln*).Slc38a8mutant mice exhibit wild-type eye and coat pigmentation with comparable melanin contents. Subcellular abnormalities were observed in retinal pigment epithelium cells ofSlc38a8mutant mice. Anterograde labelling experiments of retinal projections in embryos and adults showed a reduction of ipsilateral fibers. Functional visual analyses revealed a decreased ERG response in scotopic conditions and a reduction of visual acuity in mutant mice measured by OT.ConclusionsSlc38a8mutant mice recapitulate the phenotype of FHONDA patients concerning their normal pigmentation and their abnormal visual system, as observed in all types of albinism. These mice will be helpful in better understanding the pathophysiology of this genetic condition.