Loss of ATRAID in Late-Onset, Non-Syndromic Retinitis Pigmentosa.

Purpose: To identify and characterize a novel gene variant associated with late-onset, non-syndromic retinitis pigmentosa (RP). Methods: Ophthalmological examination included Goldmann perimetry, optical coherence tomography, fundus autofluorescence and full-field electroretinography. Gene variants were identified using whole exome sequencing. Expression of ATRAID in fibroblasts was studied using immunoblot analysis and quantitative PCR. Lysosomes were identified in ATRAID-/- and SLC37A3-/- cells using immunofluorescence analysis. Uptake of fluorescent dextran was measured using immunofluorescence analysis and flow cytometry. Results: We first examined two siblings whose parents were second cousins. Ophthalmological examination revealed symmetrical midperipheral chorioretinal atrophy with bone spicules and vessel attenuation and a corresponding rod-cone dysfunction on full-field electroretinography consistent with RP. Whole exome sequencing identified a novel homozygous variant in the ATRAID gene (NM_001170795, c.120dup, p.Ser41Glufs*13) within a 12.45 Mb region of homozygosity, predicted to result in a premature stop codon. Immunoblot analysis confirmed protein absence, indicating a loss of function variant. Further analysis of individuals with similar clinical features identified this variant in a homozygous state in four additional affected individuals in three non-consanguineous families. ATRAID has been shown to interact with SLC37A3 in lysosomes. Recently, loss of SLC37A3 has been associated with non-syndromic RP with features resembling those seen in loss of ATRAID. Increased numbers of lysosomes and accumulation of fluorescein-labelled dextran were observed both in ATRAID-/- and SLC37A3-/- cells. Conclusions: We propose that biallelic loss of ATRAID causes RP through the disruption of ATRAID and SLC37A3 interaction resulting in impaired endocytic trafficking and lysosomal function.