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A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report

Choroideremia is an X-linked recessive condition presenting in males, with progressive degeneration of retinal and choroidal tissues leading to progressive visual loss. Its pathological mechanism is due to alterations in the CHM gene that encodes for REP1, a protein required for prenylation of Rab b...

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Autores principales: Di Giosaffatte, Niccolò, Valiante, Michele, Tricarico, Stefano, Parise, Giulia, De Negri, Anna Maria, Ricciotti, Guido, Florean, Lara, Paiardini, Alessandro, Bottillo, Irene, Grammatico, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9321261/
https://www.ncbi.nlm.nih.gov/pubmed/35886051
http://dx.doi.org/10.3390/genes13071268
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author Di Giosaffatte, Niccolò
Valiante, Michele
Tricarico, Stefano
Parise, Giulia
De Negri, Anna Maria
Ricciotti, Guido
Florean, Lara
Paiardini, Alessandro
Bottillo, Irene
Grammatico, Paola
author_facet Di Giosaffatte, Niccolò
Valiante, Michele
Tricarico, Stefano
Parise, Giulia
De Negri, Anna Maria
Ricciotti, Guido
Florean, Lara
Paiardini, Alessandro
Bottillo, Irene
Grammatico, Paola
author_sort Di Giosaffatte, Niccolò
collection PubMed
description Choroideremia is an X-linked recessive condition presenting in males, with progressive degeneration of retinal and choroidal tissues leading to progressive visual loss. Its pathological mechanism is due to alterations in the CHM gene that encodes for REP1, a protein required for prenylation of Rab by the Rab geranylgeranyl transferase (RGGT). Even though female carriers are predicted to be not affected by the disease, a wide phenotypic spectrum ranging from mild to severe cases has been reported in women. The reason why Choroideremia manifests in female carriers remains elusive. While X chromosome inactivation (XCI) skewing has been proposed as a leading putative mechanism, emerging evidence has shown that CHM could variably escape from XCI. We described a family with an initial clinical suspicion of Retinitis Pigmentosa in which a novel CHM pathogenic splicing variant was found by exome sequencing. The variant, initially found in the 63-year-old female presenting with impaired visual acuity and severe retinal degeneration, segregated in the 31-year-old daughter and the 37-year-old son, both presenting with fundus anomalies. mRNA studies revealed a shorter in-frame CHM isoform lacking exon 10. Molecular modeling of the ternary REP1/Rab/RGGT protein complex predicted significant impairing of REP1/Rab binding without alteration of REP1/RGGT interaction. We suggest that, in our female cases, the biallelic expression of CHM may have led to the production of both the mutant and wild type REP1. The mutant isoform, sequestrating RGGT, could reduce its available amount for Rab prenylation, thus exerting a dominant-negative effect. If confirmed with further studies and in large cohorts of female carriers, the here proposed molecular mechanism could help to explain the complexity of manifestation of Choroideremia in females.
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spelling pubmed-93212612022-07-27 A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report Di Giosaffatte, Niccolò Valiante, Michele Tricarico, Stefano Parise, Giulia De Negri, Anna Maria Ricciotti, Guido Florean, Lara Paiardini, Alessandro Bottillo, Irene Grammatico, Paola Genes (Basel) Article Choroideremia is an X-linked recessive condition presenting in males, with progressive degeneration of retinal and choroidal tissues leading to progressive visual loss. Its pathological mechanism is due to alterations in the CHM gene that encodes for REP1, a protein required for prenylation of Rab by the Rab geranylgeranyl transferase (RGGT). Even though female carriers are predicted to be not affected by the disease, a wide phenotypic spectrum ranging from mild to severe cases has been reported in women. The reason why Choroideremia manifests in female carriers remains elusive. While X chromosome inactivation (XCI) skewing has been proposed as a leading putative mechanism, emerging evidence has shown that CHM could variably escape from XCI. We described a family with an initial clinical suspicion of Retinitis Pigmentosa in which a novel CHM pathogenic splicing variant was found by exome sequencing. The variant, initially found in the 63-year-old female presenting with impaired visual acuity and severe retinal degeneration, segregated in the 31-year-old daughter and the 37-year-old son, both presenting with fundus anomalies. mRNA studies revealed a shorter in-frame CHM isoform lacking exon 10. Molecular modeling of the ternary REP1/Rab/RGGT protein complex predicted significant impairing of REP1/Rab binding without alteration of REP1/RGGT interaction. We suggest that, in our female cases, the biallelic expression of CHM may have led to the production of both the mutant and wild type REP1. The mutant isoform, sequestrating RGGT, could reduce its available amount for Rab prenylation, thus exerting a dominant-negative effect. If confirmed with further studies and in large cohorts of female carriers, the here proposed molecular mechanism could help to explain the complexity of manifestation of Choroideremia in females. MDPI 2022-07-17 /pmc/articles/PMC9321261/ /pubmed/35886051 http://dx.doi.org/10.3390/genes13071268 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Di Giosaffatte, Niccolò
Valiante, Michele
Tricarico, Stefano
Parise, Giulia
De Negri, Anna Maria
Ricciotti, Guido
Florean, Lara
Paiardini, Alessandro
Bottillo, Irene
Grammatico, Paola
A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report
title A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report
title_full A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report
title_fullStr A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report
title_full_unstemmed A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report
title_short A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report
title_sort novel hypothesis on choroideremia-manifesting female carriers: could chm in-frame variants exert a dominant negative effect? a case report
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9321261/
https://www.ncbi.nlm.nih.gov/pubmed/35886051
http://dx.doi.org/10.3390/genes13071268
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