Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing their Potential for Retinal Gene Therapy.

Anika Nanda,Susan M Downes,Anna P Salvetti,Robert E Maclaren,Penny Clouston

doi:10.3390/genes9120643

Abstract

Inherited retinal degenerations are the leading cause of blindness in the working population. X-linked retinitis pigmentosa (XLRP), caused by mutations in the Retinitis pigmentosa GTPase regulator (RPGR) gene is one of the more severe forms, and female carriers of RPGR mutations have a variable presentation. A retrospective review of twenty-three female RPGR carriers aged between 8 and 76 years old was carried out using fundoscopy, autofluorescence imaging (AF), blue reflectance (BR) imaging and optical coherence tomography (OCT). Confirmation of the genetic mutation was obtained from male relatives or Sanger genetic sequencing. Fundus examination and AF demonstrate phenotypic variability in RPGR carriers. The genetic mutation appears indeterminate of the degree of change. We found four distinct classifications based on AF images to describe RPGR carriers; normal (N) representing normal or near-normal AF appearance (n = 1, 4%); radial (R) pattern reflex without pigmentary retinopathy (n = 14, 61%); focal (F) pigmentary retinopathy (n = 5, 22%) and; male (M) phenotype (n = 3, 13%). The phenotypes were precisely correlated in both eyes (rs = 1.0, p < 0.0001). Skewed X-inactivation can result in severely affected carrier females—in some cases indistinguishable from the male pattern and these patients should be considered for RPGR gene therapy. In the cases of the male (M) phenotype where the X-inactivation was skewed, the pattern was similar in both eyes, suggesting that the mechanism is not truly random but may have an underlying genetic basis.

Highlights

Retinitis pigmentosa is the most-common inherited retinal dystrophy with a worldwide prevalence of 1 in 4000
Differences in the fundus appearance on B-autofluorescence imaging (AF) and blue reflectance (BR) imaging allowed us to identify four different patterns of presentation: N-pattern—normal or near-normal fundus appearance, the R-pattern—radial-spoke shaped reflexes extending from the central macular area in a radial pattern; the F-pattern—focal pigmentary retinopathy patchy pigmentation with a radial reflex pattern and the
We describe the spectrum of retinal degeneration in 23 female carriers of X-linked RP

Summary

Introduction

Retinitis pigmentosa is the most-common inherited retinal dystrophy with a worldwide prevalence of 1 in 4000. It is a heterogeneous group of disorders that can be inherited as autosomal dominant (30%–40% of cases), autosomal recessive (50%–60% of cases) or X-linked (5%–15%) [1]. RPGR-related RP is one of the most severe forms of retinitis pigmentosa in males, with symptoms of nyctalopia within the first 10 years of life and progression to blindness within the third or fourth decade [3]. Despite the X-linked inheritance of RPGR, the severe phenotype can be seen in female carriers [5] and is caused by the preferential inactivation of the normal X chromosome [6]. X-linked RP can, be mistakenly characterised as autosomal dominant with every generation, including females, showing typical disease characteristics [7]

Methods

Results

Conclusion