Retinal Histopathology in Eyes from a Patient with Digenic Usher Syndrome Caused by Mutations in USH2A and GPR98.

Abstract

Purpose: To define the histopathological features in donor eyes from a patient with Usher syndrome type 2 caused by mutations in USH2A and GPR98.

Methods: Eyes were obtained from a 60 year-old female and were fixed within 25 hours from death. Globes were evaluated with macroscopic, SLO and OCT imaging. Perifoveal and peripheral retinal regions were processed for electron microscopy and immunocytochemistry using cell-specific antibodies. Three age-matched (61, 65, and 70 year old) normal eyes were used as controls. DNA was obtained from blood samples of the donor and analyzed using the OtoSCOPE® platform that includes 66 of the most common hearing loss genes. Segregation analysis was performed by testing the donor’s affected son and unaffected daughter’s samples for the two mutations identified in the donor.

Results: DNA analysis of the donor identified a heterozygous p.Gly2109Ser mutation in USH2A and a heterozygous p.Gln4989Stop mutation in GPR98. The donor’s affected son also carried these two mutations. The donor's unaffected daughter did not carry either. AF-SLO was unable to delineate the macular lutea pigment and showed some mild degeneration around the optic disk. OCT showed areas around the fovea and optic disk with a thin photoreceptor layer. The peripheral retina was still intact, but lacked structural features (i.e. an ellipsoid band). In the periphery, histology showed distinct GCL and INL, but the ONL was reduced to 3-5 nuclear rows. In addition, several patchy areas of photoreceptor loss were noted. Prominent GCL and INL were present in the perifoveal retina, but the ONL retained only scattered nuclei. The RPE was thin but the choriocapillaris was present and robust. No cone opsin or cone arrestin labeled cells were observed in the macula, but a few highly disorganized cone-specific cells were present in the periphery. No rhodopsin-positive cells were observed in the macula, but were evident in the peripheral retina.

Conclusions: The histopathology of the retina in a patient with Usher syndrome due to digenic USH2A and GPR98 mutations displayed a highly degenerated perifoveal retina with preservation of some peripheral cone and rod photoreceptors. To our knowledge, digenic Usher syndrome has not been previously described due to molecular interactions between the USH2A and GRP98 genes.

Keywords: 696 retinal degenerations: hereditary • 539 genetics • 554 immunohistochemistry