RP1L1 variants are associated with retinitis pigmentosa and occult macular dystrophy

Abstract

Purpose: Autosomal dominant mutations in the RP1L1 gene have been recently associated with occult macular dystrophy (OCMD), a condition usually characterized by progressive foveal cone dysfunction and no apparent fundoscopic or full-field electoretinogram abnormalities. Intriguingly, the Rp1l1 knockout mouse has been shown to have a phenotype consistent with retinitis pigmentosa (RP). The aim of this study is to provide insights into the clinical and genetic characteristics of OCMD and to probe whether RP1L1 mutations cause RP in man.

Methods: Twenty-eight individuals with OCMD and 286 individuals with recessive RP were recruited and screened for RP1L1. Exome sequencing was performed in a consanguineous family with RP. Sanger sequencing of the RP1 gene as well as haplotype and in silico analysis of RP1L1 variants were performed. Clinical investigations included fundus autofluorescence imaging, spectral domain optical coherence tomography (OCT) and electrophysiology.

Results: Homozygous, likely disease causing, RP1L1 variants were identified in two individuals with typical sings of RP; one carried a frameshifting (p.Lys203Argfs*28) and the other a missense (p.Ser546Thr) mutation. Ten out of twenty-eight OCMD patients were found to harbour rare (minor allele frequency ≤0.5% in the 1,000 genomes dataset) heterozygous RP1L1 variants. Irregular foveal fundus autofluorescence was evident in 6 of 10 cases. Spectral domain OCT showed focal disruption of the outer retina in 8 of 9 cases. Full-field electroretinograms were normal in 8 and revealed mild generalised cone system dysfunction in 2 individuals. Analysis of family members revealed unaffected relatives harbouring the same variant. Linkage analysis excluded recessive inheritance, and sequencing of RP1, a gene encoding a photoreceptor protein that interacts with RP1L1, excluded a potential digenic mechanism.

Conclusions: Biallelic RP1L1 variants can be associated with recessive RP in man. OCMD is a pathogenetically heterogeneous macular dystrophy and heterozygous RP1L1 variants cause OCMD with incomplete penetrance; the disorder is not Mendelian and is likely to have a complex pathology with contribution from other genetic and environmental factors.

Keywords: 696 retinal degenerations: hereditary • 539 genetics • 537 gene screening