As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene

Mutations in the TCIRG1 gene, coding for a subunit of the osteoclast proton pump, are responsible for more than 50% of cases of human malignant autosomal recessive osteopetrosis (ARO), a rare inherited bone disease with increased bone density owing to a failure in bone resorption. A wide variety of...

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Autores: Sobacchi, Cristina, Pangrazio, Alessandra, González-Meneses López, Antonio, Pascual-Vaca Gómez, Diego, Caldana, Maria Elena, Susani, Lucia, Vezzoni, Paolo, Villa, Anna
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Recursos:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/172787
Acesso em linha:https://hdl.handle.net/11441/172787
https://doi.org/10.1002/jbmr.2203
Access Level:acceso abierto
Palavra-chave:autosomal recessive osteopetrosis
TCIRG1
hypomorphic mutation
splicing defect
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spelling As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 GeneSobacchi, CristinaPangrazio, AlessandraGonzález-Meneses López, AntonioPascual-Vaca Gómez, DiegoCaldana, Maria ElenaSusani, LuciaVezzoni, PaoloVilla, Annaautosomal recessive osteopetrosisTCIRG1hypomorphic mutationsplicing defectMutations in the TCIRG1 gene, coding for a subunit of the osteoclast proton pump, are responsible for more than 50% of cases of human malignant autosomal recessive osteopetrosis (ARO), a rare inherited bone disease with increased bone density owing to a failure in bone resorption. A wide variety of mutations has been described, including missense, nonsense, small deletions/insertions, splice‐site mutations, and large genomic deletions, all leading to a similar severe presentation. So far, to the best of our knowledge, no report of a mild phenotype owing to recessive TCIRG1 mutations is present neither in our series of more than 100 TCIRG1‐dependent ARO patients nor in the literature. Here we describe an 8‐year‐old patient referred to us with a clinical diagnosis of ARO, based on radiological findings; of note, no neurological or hematological defects were present in this girl. Surprisingly, we identified a novel nucleotide change in intron 15 of the TCIRG1 gene at the homozygous state, leading to the production of multiple aberrant transcripts, but also, more importantly, of a limited amount of the normal transcript. Our results show that a low level of normal TCIRG1 protein can dampen the clinical presentation of TCIRG1‐dependent ARO. On this basis, a small amount of protein might be sufficient to rescue, at least partially, the severe ARO phenotype, and this is particularly important when gene therapy approaches are considered. In addition, we would also recommend that the TCIRG1 gene be included in the molecular diagnosis of mild forms of human ARO. © 2014 Italian National Research Council. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.Oxford University PressFarmacología, Pediatría y RadiologíaEuropean UnionGiovani Ricercatori from Ministero della SalutePNR-CNR Aging ProgramPRIN ProjectRicerca Finalizzata from Ministero della saluteTelethon Foundation2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/172787https://doi.org/10.1002/jbmr.2203reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésJournal of Bone and Mineral Research, 29 (7), 1646-1650.GR-2008-1134625200999KRFW-00220102M7T8X_003RF-2009-1499; 542GGP12178https://academic.oup.com/jbmr/article/29/7/1646/7598977info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1727872026-06-17T12:51:07Z
dc.title.none.fl_str_mv As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene
title As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene
spellingShingle As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene
Sobacchi, Cristina
autosomal recessive osteopetrosis
TCIRG1
hypomorphic mutation
splicing defect
title_short As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene
title_full As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene
title_fullStr As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene
title_full_unstemmed As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene
title_sort As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene
dc.creator.none.fl_str_mv Sobacchi, Cristina
Pangrazio, Alessandra
González-Meneses López, Antonio
Pascual-Vaca Gómez, Diego
Caldana, Maria Elena
Susani, Lucia
Vezzoni, Paolo
Villa, Anna
author Sobacchi, Cristina
author_facet Sobacchi, Cristina
Pangrazio, Alessandra
González-Meneses López, Antonio
Pascual-Vaca Gómez, Diego
Caldana, Maria Elena
Susani, Lucia
Vezzoni, Paolo
Villa, Anna
author_role author
author2 Pangrazio, Alessandra
González-Meneses López, Antonio
Pascual-Vaca Gómez, Diego
Caldana, Maria Elena
Susani, Lucia
Vezzoni, Paolo
Villa, Anna
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Farmacología, Pediatría y Radiología
European Union
Giovani Ricercatori from Ministero della Salute
PNR-CNR Aging Program
PRIN Project
Ricerca Finalizzata from Ministero della salute
Telethon Foundation
dc.subject.none.fl_str_mv autosomal recessive osteopetrosis
TCIRG1
hypomorphic mutation
splicing defect
topic autosomal recessive osteopetrosis
TCIRG1
hypomorphic mutation
splicing defect
description Mutations in the TCIRG1 gene, coding for a subunit of the osteoclast proton pump, are responsible for more than 50% of cases of human malignant autosomal recessive osteopetrosis (ARO), a rare inherited bone disease with increased bone density owing to a failure in bone resorption. A wide variety of mutations has been described, including missense, nonsense, small deletions/insertions, splice‐site mutations, and large genomic deletions, all leading to a similar severe presentation. So far, to the best of our knowledge, no report of a mild phenotype owing to recessive TCIRG1 mutations is present neither in our series of more than 100 TCIRG1‐dependent ARO patients nor in the literature. Here we describe an 8‐year‐old patient referred to us with a clinical diagnosis of ARO, based on radiological findings; of note, no neurological or hematological defects were present in this girl. Surprisingly, we identified a novel nucleotide change in intron 15 of the TCIRG1 gene at the homozygous state, leading to the production of multiple aberrant transcripts, but also, more importantly, of a limited amount of the normal transcript. Our results show that a low level of normal TCIRG1 protein can dampen the clinical presentation of TCIRG1‐dependent ARO. On this basis, a small amount of protein might be sufficient to rescue, at least partially, the severe ARO phenotype, and this is particularly important when gene therapy approaches are considered. In addition, we would also recommend that the TCIRG1 gene be included in the molecular diagnosis of mild forms of human ARO. © 2014 Italian National Research Council. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
publishDate 2014
dc.date.none.fl_str_mv 2014
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://hdl.handle.net/11441/172787
https://doi.org/10.1002/jbmr.2203
url https://hdl.handle.net/11441/172787
https://doi.org/10.1002/jbmr.2203
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Journal of Bone and Mineral Research, 29 (7), 1646-1650.
GR-2008-1134625
200999KRFW-002
20102M7T8X_003
RF-2009-1499; 542
GGP12178
https://academic.oup.com/jbmr/article/29/7/1646/7598977
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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