Is solute carrier protein (SC1) a novel gene for autosomal recessive retinitis pigmentosa?

Abstract

Purpose: Autosomal recessive retinitis pigmentosa (arRP) is a severe, clinically and genetically heterogeneous, retinal disease that leads to blindness. Approximately 50% of RP patients have mutations in known genes. Our goal is to identify the remaining RP genes. We have identified nine unrelated patients with a clinical phenotype of arRP who are genetically unsettled. In this study we aim to identify their causal gene.

Methods: In one arRP proband, we used a RetNet chip to exclude mutations in known genes and subsequently subjected her DNA to whole exome sequencing by next generation sequencing. We identified two deleterious mutations in a novel solute carrier (SC1). We then tested a second RP cohort with the same cultural background and found mutations in five more families. In a Quebec RP cohort, we identified mutations in another three families. In affected patients with one mutation, we tested the digenic, trigenic, and quadrigenic hypotheses by sequencing related solute carrier proteins (SC2, SC3 and SC4). We are revisiting the ocular and subclinical systemic phenotypes. All mutations are characterized in silico by using SIFT, polyphen, and Blosum.

Results: We have found novel mutations in all four genes (SC1, SC2, SC3, SC4). Mutations in SC1 are found in all 9 patients, those in SC2 are found in 7 patients, and those in SC3 and SC4 are found in 1 patient. One patient has mutations in 1 out of 4 genes, three patients have mutations in 2 genes, two patients have mutations in 3 genes, and three patients have mutations in 4 genes. Multiple mutations demonstrate residues conserved down to zebrafish and drosophila.

Conclusions: We believe that we have identified a new gene and a novel pathway for retinitis pigmentosa. We are currently investigating the full extent of the mutation spectrum and severity and will conduct mutagenesis studies and functional testing. Our findings are crucial in expanding the current understanding of hereditary retinal degenerations and in developing new potential therapies.

Keywords: 696 retinal degenerations: hereditary • 648 photoreceptors • 539 genetics