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

To identify and characterize a novel gene variant associated with late-onset, non-syndromic retinitis pigmentosa (RP).

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.

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.

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.