SLC24A1 mutations are a cause of autosomal recessive retinitis pigmentosa

Abstract

Purpose : To determine the retinal phenotype in patients with biallelic variants in SLC24A1, originally described as a cause of Riggs-type congenital stationary night blindness (CSNB).

Methods : Multicentre, retrospective case series. Sixteen individuals with retinal dysfunction attributed to biallelic variants in SLC24A1 on molecular genetic testing were identified, including five individuals previously reported with CSNB. The retinal phenotype was characterized by colour fundus photography, short-wavelength fundus autofluoresence imaging, and optical coherence tomography of both the macula and peripheral retina. Full-field electroretinography and visual field testing were also undertaken in some patients. Protein modelling was used to predict the likely functional effects of non-truncating SLC24A1 variants.

Results : Fifteen individuals, 18 to 59 years old, showed retinal features characteristic of a progressive rod-cone degeneration (retinitis pigmentosa; RP). These patients usually experienced night blindness in childhood and demonstrated relatively mild structural changes for their age. They harboured 2 truncating SLC24A1 mutations, or rare missense variants with severe functional effects as predicted by protein modelling. One 39-year-old patient with a truncating SLC24A1 variant and an in-frame deletion c.1691_1693del, p.(Phe564del) in trans had a phenotype of CSNB. Protein modelling of the SLC24A1-encoded ion exchanger predicted p.(Phe564del) to have a mild effect on the outfacing alpha-helix of a transmembrane domain, supporting the hypothesis that hypomorphic variants in SLC24A1 might result in a Riggs-type CSNB phenotype.

Conclusions : This study identifies SLC24A1 variants as a cause of autosomal recessive RP, aligning it with other rod channelopathies and the knock-out mouse model, which are typified by early rod dysfunction and slow retinal degeneration. SLC24A1 should be included in molecular genetic testing panels for RP. SLC24A1 should also be screened for in patients with CSNB because early degenerative changes may not yet have become manifest or may have been missed, and because there may be a role for hypomorphic SLC24A1 alleles in the pathogenesis of CSNB. Individuals with biallelic nullizygous variants in SLC24A1 should be counselled regarding the progressive nature of the disease.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Classic RP with biallelic SLC24A1 mutations

 

SLC24A1-associated RP with degenerative features visible only in the peripheral retina