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

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.

RPGR-Associated Dystrophies: Clinical, Genetic, and Histopathological Features

“…It is believed that frameshift mutations in the exons that encode the N-terminal RCC1-like domain of RPGR are more prone to nonsense-mediated decay (NMD), leading to lower levels of the transcript and may therefore be more likely to cause severe RP phenotypes [4]. Furthermore, the N-terminal RCC1-like domain of RPGR is shared between RPGR ORF15 and RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] isoforms. Since RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] is also expressed in primary cilia, it is believed that mutations in the N-terminal RCC1-like domain may lead to retinal degeneration with ciliary abnormalities, as shown in previous studies [33][34][35].…”

“…Symptom onset in affected males starts in childhood years and is described to reach blindness within the 4th decade of life [2,7,8]. Despite the X-linked inheritance of RPGR, female carriers may also be affected by XLRP [9,10].…”

“…The RPGR gene encodes the retinitis pigmentosa GTPase regulator (RPGR) protein and is able to express multiple isoforms through alternative splicing. The most common protein isoforms found in the retina are RPGR ORF15 and, to a lesser extent, the constitutive protein RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] [13,14]. The RPGR ORF15 transcript, which is believed to play a key role in intraflagellar transport processes, contains exon 1-14 and exon ORF15, which is formed by alternatively spliced exon 15 and intron 15 [15].…”

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

“…The patient with an absence of bone spicule pigmentation was relatively young and carried disease‐causing mutations in CDHR1 , which is known to cause a delayed‐onset retinal degeneration; thus, the patient will likely develop bone spicule pigmentation later in life . Asymmetric disease manifestation was observed in two female patients with sporadic RP in whom only one eye was suggestive for their X‐linked carrier status, likely due to skewed X‐inactivation in the more severely affected eye . The uncommon findings on retinal imaging in patients without identified mutations could reflect atypical genotype‐phenotype correlations, specific effects of as yet unidentified disease‐causing genetic variants, and/or non‐genetic phenocopies as indicated above.…”

“…11,36 Asymmetric disease manifestation was observed in two female patients with sporadic RP in whom only one eye was suggestive for their X-linked carrier status, likely due to skewed X-inactivation in the more severely affected eye. 37 The uncommon findings on retinal imaging in patients without identified mutations could reflect atypical genotype-phenotype correlations, specific effects of as yet genetic testing may increase the likelihood to identify disease-causing mutations. The proportion of genetically solved patients is illustrated in grey, and the proportion genetically unsolved patients is illustrated in black.…”