Two distinct phenotypes in the same family are caused by the Schiff base counterion mutation p.E113K in rhodopsin.

Abstract

Purpose : Retinitis pigmentosa (RP) and congenital stationary night blindness (CSNB) are rarely found as independent phenotypes within the same family. The current study aimed to identify a causative mutation in a RP-affected index patient and in several older members of the same family affected with an incomplete form of CSNB.

Methods : One RP-affected index patient, five CSNB-affected members and one healthy relative of a three-generation family participated in this study. A full phenotypic characterization of the index patient and CSNB-affected relatives was performed (e.g., visual acuity, funduscopy, Goldmann perimetry, and electroretinograms (ERG)). Whole exome sequencing was performed to screen for mutations in the index patient and in two CSNB-affected relatives. Sanger sequencing was applied to verify genomic variants within the family and in 199 unrelated controls.

Results : Ophthalmological examinations of the index patient confirmed the diagnosis of RP, including midperipheral loss of choriocapillaris, constricted retinal vessels, isolated retinal vessel-associated pigmentary clumping and foveal thinning. ERG showed pathologically reduced minor amplitudes in both eyes. In contrast, clinical characterizations and ERGs of the CSNB-affected family members suggested an incomplete form of CSNB (Schubert-Bornschein type). Using whole exome sequencing, the non-synonymous substitution c.337G>A, p.E113K was found in the rhodopsin (RHO) gene. The identification of the pathogenic variant p.E113K is the first description of a naturally-occurring mutation in the Schiff base counterion of RHO in human patients. The heterozygous mutation c.337G>A in exon 1 co-segregated with the phenotype in all family members, including the index patient and five CSNB-affected relatives. Additional RHO variants were not detected in the patients. The mutation was excluded in the healthy family member and in 199 ethnically matched controls. Exome sequencing suggested genetic modifiers, which might explain the more severe phenotype of the RP-affected index patient.

Conclusions : Our findings demonstrate that the mutation of the biochemically well-characterized counterion p.E113 in RHO may cause either RP or incomplete CSNB, even within the same family.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.