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

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 pres...

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Autores principales: Nanda, Anika, Salvetti, Anna P., Clouston, Penny, Downes, Susan M., MacLaren, Robert E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316369/
https://www.ncbi.nlm.nih.gov/pubmed/30567410
http://dx.doi.org/10.3390/genes9120643
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author Nanda, Anika
Salvetti, Anna P.
Clouston, Penny
Downes, Susan M.
MacLaren, Robert E.
author_facet Nanda, Anika
Salvetti, Anna P.
Clouston, Penny
Downes, Susan M.
MacLaren, Robert E.
author_sort Nanda, Anika
collection PubMed
description 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.
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spelling pubmed-63163692019-01-09 Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy Nanda, Anika Salvetti, Anna P. Clouston, Penny Downes, Susan M. MacLaren, Robert E. Genes (Basel) Article 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. MDPI 2018-12-18 /pmc/articles/PMC6316369/ /pubmed/30567410 http://dx.doi.org/10.3390/genes9120643 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nanda, Anika
Salvetti, Anna P.
Clouston, Penny
Downes, Susan M.
MacLaren, Robert E.
Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy
title Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy
title_full Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy
title_fullStr Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy
title_full_unstemmed Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy
title_short Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy
title_sort exploring the variable phenotypes of rpgr carrier females in assessing their potential for retinal gene therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316369/
https://www.ncbi.nlm.nih.gov/pubmed/30567410
http://dx.doi.org/10.3390/genes9120643
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