Dominant Mutations in RP1L1 Are Responsible for Occult Macular Dystrophy

Abstract

Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.

Clinical Characteristics of Occult Macular Dystrophy in Family With Mutation of Rp1l1 Gene

“…A homozygous mutation, p.Arg45Trp in the RP1L1 gene, was confirmed in 14 members, 12 and 13 of the 14 were diagnosed with OMD. Among the 14 members with a mutation in the RP1L1 gene, 11 were followed-up at the Niigata University in Niigata, Japan.…”

“…18 However, the RP1L1 protein has a very low degree of overall sequence identity (39%) between humans and mice compared with the average values of sequence similarity observed between humans and mice proteins. The results of linkage studies have strongly supported the contribution of RP1L1 mutations to the presence of this disease, 12 but the function of RP1L1 in the human retina has not been completely determined.…”

“…[6][7][8][9][10][11] Recently, we found that dominant mutations in the RP1L1 gene were responsible for OMD. 12 The RP1L1 gene was originally cloned as a gene derived from common ancestors as a retinitis pigmentosa 1 (RP1) gene, which is responsible for 5-10% of autosomal dominant retinitis pigmentosa worldwide, on the same Chromosome 8. [13][14][15][16][17] A number of attempts have been made to identify mutations in RP1L1 in various retinitis pigmentosa patients with no success.…”

The role of primary cilia in the development and disease of the retina

“…59 Loss of this protein in humans is associated with occult macular dystrophy (OMD) and RP. 60,61 Myosin 7a, that is mutated in both Leber congenital amaurosis (LCA), an early-onset retinal dystrophy, 62 and Usher syndrome type 1B 63 is also localized to the site of disc morphogenesis. Myosin 7a plays a role in transport of proteins from the IS to the OS for incorporation into discs, and opsin accumulates in the IS of Myo7a mutant mouse.…”

Identification of rod- and cone-specific expression signatures to identify candidate genes for retinal disease

“…While the underlying gene has been identified in a significant number of cases (212, as of March 2014), the proportion of unknown causal variants has remained relatively steady at approximately 15e20% (RetNet, http://www.sph.uth.tmc.edu/RetNet) (Daiger et al, 1998). Traditionally, causal genes have been cloned via a process of linkage analysis followed by candidate gene screening in large families (for example (Akahori et al, 2010;Li et al, 2004Li et al, , 2010). However, this has not always been successful, not least because the linkage regions may be large and contain many genes (Chaib et al, 1997;Ismail et al, 2006;Yang et al, 2006).…”