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Skewed X-inactivation is associated with retinal dystrophy in female carriers of RPGR mutations

Progressive degeneration of rod and cone photoreceptors frequently is caused by mutations in the X-chromosomal gene Retinitis Pigmentosa GTPase Regulator (RPGR). Males hemizygous for a RPGR mutation often are affected by Retinitis Pigmentosa (RP), whereas female mutation carriers only occasionally p...

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Autores principales: Usman, Muhammad, Jüschke, Christoph, Song, Fei, Kastrati, Dennis, Owczarek-Lipska, Marta, Eilers, Jannis, Pauleikhoff, Laurenz, Lange, Clemens, Neidhardt, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10403639/
https://www.ncbi.nlm.nih.gov/pubmed/37541846
http://dx.doi.org/10.26508/lsa.202201814
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author Usman, Muhammad
Jüschke, Christoph
Song, Fei
Kastrati, Dennis
Owczarek-Lipska, Marta
Eilers, Jannis
Pauleikhoff, Laurenz
Lange, Clemens
Neidhardt, John
author_facet Usman, Muhammad
Jüschke, Christoph
Song, Fei
Kastrati, Dennis
Owczarek-Lipska, Marta
Eilers, Jannis
Pauleikhoff, Laurenz
Lange, Clemens
Neidhardt, John
author_sort Usman, Muhammad
collection PubMed
description Progressive degeneration of rod and cone photoreceptors frequently is caused by mutations in the X-chromosomal gene Retinitis Pigmentosa GTPase Regulator (RPGR). Males hemizygous for a RPGR mutation often are affected by Retinitis Pigmentosa (RP), whereas female mutation carriers only occasionally present with severe RP phenotypes. The underlying pathomechanism leading to RP in female carriers is not well understood. Here, we analyzed a three-generation family in which two of three female carriers of a nonsense RPGR mutation presented with RP. Among two cell lines derived from the same female family members, differences were detected in RPGR transcript expression, in localization of RPGR along cilia, as well as in primary cilium length. Significantly, these differences correlated with alterations in X-chromosomal inactivation patterns found in the patient-derived cell lines from females. In summary, our data suggest that skewed X-chromosomal inactivation is an important factor that determines the disease manifestation of RP among female carriers of pathogenic sequence alterations in the RPGR gene.
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spelling pubmed-104036392023-08-06 Skewed X-inactivation is associated with retinal dystrophy in female carriers of RPGR mutations Usman, Muhammad Jüschke, Christoph Song, Fei Kastrati, Dennis Owczarek-Lipska, Marta Eilers, Jannis Pauleikhoff, Laurenz Lange, Clemens Neidhardt, John Life Sci Alliance Research Articles Progressive degeneration of rod and cone photoreceptors frequently is caused by mutations in the X-chromosomal gene Retinitis Pigmentosa GTPase Regulator (RPGR). Males hemizygous for a RPGR mutation often are affected by Retinitis Pigmentosa (RP), whereas female mutation carriers only occasionally present with severe RP phenotypes. The underlying pathomechanism leading to RP in female carriers is not well understood. Here, we analyzed a three-generation family in which two of three female carriers of a nonsense RPGR mutation presented with RP. Among two cell lines derived from the same female family members, differences were detected in RPGR transcript expression, in localization of RPGR along cilia, as well as in primary cilium length. Significantly, these differences correlated with alterations in X-chromosomal inactivation patterns found in the patient-derived cell lines from females. In summary, our data suggest that skewed X-chromosomal inactivation is an important factor that determines the disease manifestation of RP among female carriers of pathogenic sequence alterations in the RPGR gene. Life Science Alliance LLC 2023-08-04 /pmc/articles/PMC10403639/ /pubmed/37541846 http://dx.doi.org/10.26508/lsa.202201814 Text en © 2023 Usman et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Usman, Muhammad
Jüschke, Christoph
Song, Fei
Kastrati, Dennis
Owczarek-Lipska, Marta
Eilers, Jannis
Pauleikhoff, Laurenz
Lange, Clemens
Neidhardt, John
Skewed X-inactivation is associated with retinal dystrophy in female carriers of RPGR mutations
title Skewed X-inactivation is associated with retinal dystrophy in female carriers of RPGR mutations
title_full Skewed X-inactivation is associated with retinal dystrophy in female carriers of RPGR mutations
title_fullStr Skewed X-inactivation is associated with retinal dystrophy in female carriers of RPGR mutations
title_full_unstemmed Skewed X-inactivation is associated with retinal dystrophy in female carriers of RPGR mutations
title_short Skewed X-inactivation is associated with retinal dystrophy in female carriers of RPGR mutations
title_sort skewed x-inactivation is associated with retinal dystrophy in female carriers of rpgr mutations
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10403639/
https://www.ncbi.nlm.nih.gov/pubmed/37541846
http://dx.doi.org/10.26508/lsa.202201814
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