A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.

BACKGROUND: Mutations in the GBA gene that encodes the lysosomal enzyme acid ß-glucocerebrosidase cause Gaucher disease (GD), the most common lysosomal storage disorder. Most of the mutations are missense/nonsense, however, a few splicing mutations within or close to conserved consensus donor or acc...

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Autores: Malekkou A, Sevastou I, Mavrikiou G, Georgiou T, Vilageliu L, Moraitou M, Michelakakis H, Prokopiou C, Drousiotou A
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p17253
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=17253
https://onlinelibrary.wiley.com/doi/epdf/10.1002/mgg3.1090
Access Level:acceso abierto
Palabra clave:* GBA
*Cypriot
*Gaucher disease
*deep intronic mutation
*glucocerebrosidase
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spelling A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.Malekkou ASevastou IMavrikiou GGeorgiou TVilageliu LMoraitou MMichelakakis HProkopiou CDrousiotou A* GBA*Cypriot*Gaucher disease*deep intronic mutation*glucocerebrosidaseBACKGROUND: Mutations in the GBA gene that encodes the lysosomal enzyme acid ß-glucocerebrosidase cause Gaucher disease (GD), the most common lysosomal storage disorder. Most of the mutations are missense/nonsense, however, a few splicing mutations within or close to conserved consensus donor or acceptor splice sites have also been described. The aim of the study was to identify the mutation(s) in a Cypriot patient with type I GD. METHODS: The genomic DNA of the proband was screened for nine common mutations using Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. All exons and exon-intron boundaries, and the 5'UTR and 3'UTR regions of the GBA gene, were investigated by Sanger sequencing. RNA analysis was performed using standard procedures, and the abnormal transcript was further cloned into pGEM-T-Easy plasmid vector and sequenced. The relevant intronic region was further sequenced by the Sanger method to identify the genetic variant. RESULTS: A novel point mutation, g.12599C > A (c.999 + 242C > A), was detected deep in intron 7 of the GBA gene. This type of mutation has been previously described for other diseases but this is the first time, as far as we know, that it is described for GD. This mutation creates a new donor splice site leading to aberrant splicing and resulting in the insertion of the first 239nt of intron 7 as a pseudoexon in the mRNA, creating a premature stop codon. CONCLUSION: This study expands the mutation spectrum of GD and highlights the importance of RNA sequencing for the molecular diagnosis of patients bearing mutations in nonexonic regions.WILEY2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=17253https://onlinelibrary.wiley.com/doi/epdf/10.1002/mgg3.1090Molecular Genetics & Genomic MedicineISSN: 23249269reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p172532026-05-27T12:37:41Z
dc.title.none.fl_str_mv A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.
title A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.
spellingShingle A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.
Malekkou A
* GBA
*Cypriot
*Gaucher disease
*deep intronic mutation
*glucocerebrosidase
title_short A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.
title_full A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.
title_fullStr A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.
title_full_unstemmed A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.
title_sort A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.
dc.creator.none.fl_str_mv Malekkou A
Sevastou I
Mavrikiou G
Georgiou T
Vilageliu L
Moraitou M
Michelakakis H
Prokopiou C
Drousiotou A
author Malekkou A
author_facet Malekkou A
Sevastou I
Mavrikiou G
Georgiou T
Vilageliu L
Moraitou M
Michelakakis H
Prokopiou C
Drousiotou A
author_role author
author2 Sevastou I
Mavrikiou G
Georgiou T
Vilageliu L
Moraitou M
Michelakakis H
Prokopiou C
Drousiotou A
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv * GBA
*Cypriot
*Gaucher disease
*deep intronic mutation
*glucocerebrosidase
topic * GBA
*Cypriot
*Gaucher disease
*deep intronic mutation
*glucocerebrosidase
description BACKGROUND: Mutations in the GBA gene that encodes the lysosomal enzyme acid ß-glucocerebrosidase cause Gaucher disease (GD), the most common lysosomal storage disorder. Most of the mutations are missense/nonsense, however, a few splicing mutations within or close to conserved consensus donor or acceptor splice sites have also been described. The aim of the study was to identify the mutation(s) in a Cypriot patient with type I GD. METHODS: The genomic DNA of the proband was screened for nine common mutations using Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. All exons and exon-intron boundaries, and the 5'UTR and 3'UTR regions of the GBA gene, were investigated by Sanger sequencing. RNA analysis was performed using standard procedures, and the abnormal transcript was further cloned into pGEM-T-Easy plasmid vector and sequenced. The relevant intronic region was further sequenced by the Sanger method to identify the genetic variant. RESULTS: A novel point mutation, g.12599C > A (c.999 + 242C > A), was detected deep in intron 7 of the GBA gene. This type of mutation has been previously described for other diseases but this is the first time, as far as we know, that it is described for GD. This mutation creates a new donor splice site leading to aberrant splicing and resulting in the insertion of the first 239nt of intron 7 as a pseudoexon in the mRNA, creating a premature stop codon. CONCLUSION: This study expands the mutation spectrum of GD and highlights the importance of RNA sequencing for the molecular diagnosis of patients bearing mutations in nonexonic regions.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=17253
https://onlinelibrary.wiley.com/doi/epdf/10.1002/mgg3.1090
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=17253
https://onlinelibrary.wiley.com/doi/epdf/10.1002/mgg3.1090
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv WILEY
publisher.none.fl_str_mv WILEY
dc.source.none.fl_str_mv Molecular Genetics & Genomic Medicine
ISSN: 23249269
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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