DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia

Cytochrome-c oxidase (COX) is part of the mitochondrial complex IV (CIV). COX deficiency is usually associated with tRNA variants, and less frequently with variants in COX assembly factors. Mutations in COX subunits encoded by mitochondrial DNA and nuclear DNA are rare, likely because most of them a...

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Autores: Mavillard, Fabiola, Guerra-Castellano, Alejandra, Rívas, Eloy, Cantero, Gloria, Servián Morilla, E., Folland, Chiara, Ravenscroft, Gianina, Martín, Miguel A., Cabrera-Serrano, Macarena, Díaz-Moreno, Irene, Paradas-López, Carmen
Tipo de recurso: conjunto de datos
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/395317
Acceso en línea:http://hdl.handle.net/10261/395317
Access Level:acceso abierto
Palabra clave:http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
mitochondria
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oai_identifier_str oai:digital.csic.es:10261/395317
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
title DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
spellingShingle DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
Mavillard, Fabiola
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
mitochondria
title_short DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
title_full DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
title_fullStr DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
title_full_unstemmed DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
title_sort DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia
dc.creator.none.fl_str_mv Mavillard, Fabiola
Guerra-Castellano, Alejandra
Rívas, Eloy
Cantero, Gloria
Servián Morilla, E.
Folland, Chiara
Ravenscroft, Gianina
Martín, Miguel A.
Cabrera-Serrano, Macarena
Díaz-Moreno, Irene
Paradas-López, Carmen
author Mavillard, Fabiola
author_facet Mavillard, Fabiola
Guerra-Castellano, Alejandra
Rívas, Eloy
Cantero, Gloria
Servián Morilla, E.
Folland, Chiara
Ravenscroft, Gianina
Martín, Miguel A.
Cabrera-Serrano, Macarena
Díaz-Moreno, Irene
Paradas-López, Carmen
author_role author
author2 Guerra-Castellano, Alejandra
Rívas, Eloy
Cantero, Gloria
Servián Morilla, E.
Folland, Chiara
Ravenscroft, Gianina
Martín, Miguel A.
Cabrera-Serrano, Macarena
Díaz-Moreno, Irene
Paradas-López, Carmen
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Junta de Andalucía
Fundación Ramón Areces
Mavillard, Fabiola [0000-0002-1460-0483]
Guerra-Castellano, Alejandra [0000-0001-5823-1678]
Guerrero-Gómez, David [0000-0001-9403-6431]
Rívas, Eloy [0000-0001-6014-8048]
Cantero, Gloria [0000-0001-8159-9913]
Servián Morilla, E. [0000-0002-6467-9740]
Folland, Chiara [0000-0002-6346-4828]
Ravenscroft, Gianina [0000-0003-3634-211X]
Martín, Miguel A. [0000-0003-4741-772X]
Miranda-Vizuete, Antonio [0000-0002-6856-5396]
Cabrera-Serrano, Macarena [0000-0003-3109-6095]
Díaz-Moreno, Irene [0000-0002-5318-7644]
Paradas-López, Carmen [0000-0002-6917-2236]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
mitochondria
topic http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
mitochondria
description Cytochrome-c oxidase (COX) is part of the mitochondrial complex IV (CIV). COX deficiency is usually associated with tRNA variants, and less frequently with variants in COX assembly factors. Mutations in COX subunits encoded by mitochondrial DNA and nuclear DNA are rare, likely because most of them are associated to very severe phenotypes with early lethality. COX18, an assembly factor of CIV, has long been analyzed as a potential cause of mitochondrial disease. To date, only one patient has been identified carrying a homozygous missense variant in COX18, associated with neonatal encephalo-cardiomyopathy and axonal sensory neuropathy. Here, we describe a 40-year-old patient, asymptomatic until 7 months of age, who presented with progressive muscle weakness resembling spinal muscle atrophy type-2, associated with oculofacial apraxia and dysarthric speech. Electrophysiology analysis highlighted a severe sensory-motor neuropathy. Muscle biopsy showed striking and diffuse decreases of COX staining and a substantial reduction of CIV activity. Muscle biopsy showed no ragged-red fibers, although ultrastructural mitochondrial alterations were evident. A novel homozygous variant (c.598G>A), located in the last nucleotide of exon 3, was detected in COX18 by whole-exome sequencing, which affected the splicing donor site, as demonstrated by cDNA-seq. The patient fibroblasts express a truncated form of COX18 (COX18Δ112-240) capable of assembling CIV and CIV-involving supercomplexes. However, CIV activity was decreased. COX18 full-length (COX18-fl) overexpression partially rescued CIV activity in the patient fibroblasts. The rescue of the null CIV activity in COX18-KO-HEK293 cells by overexpressing of COX18Δ112-240 was significantly lower than in cells with COX18-fl. In addition, cox-18 downregulation in C. elegans resulted in slow growth and, diminished reduced motility phenotypes and as well as severe fragmentation of the mitochondrial network. Our case expands the phenotypes associated with COX18 variants and supports the pathogenic role of COX18 as the cause of a severe encephaloneuropathy syndrome
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/dataset
http://purl.org/coar/resource_type/c_ddb1
Publisher's version
info:eu-repo/semantics/publishedVersion
format dataset
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/395317
url http://hdl.handle.net/10261/395317
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PGC2018-096049-B-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-126663NB-I00
https://doi.org/10.1016/j.bbadis.2024.167330
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling DATASET A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxiaMavillard, FabiolaGuerra-Castellano, AlejandraRívas, EloyCantero, GloriaServián Morilla, E.Folland, ChiaraRavenscroft, GianinaMartín, Miguel A.Cabrera-Serrano, MacarenaDíaz-Moreno, IreneParadas-López, Carmenhttp://metadata.un.org/sdg/3Ensure healthy lives and promote well-being for all at all agesmitochondriaCytochrome-c oxidase (COX) is part of the mitochondrial complex IV (CIV). COX deficiency is usually associated with tRNA variants, and less frequently with variants in COX assembly factors. Mutations in COX subunits encoded by mitochondrial DNA and nuclear DNA are rare, likely because most of them are associated to very severe phenotypes with early lethality. COX18, an assembly factor of CIV, has long been analyzed as a potential cause of mitochondrial disease. To date, only one patient has been identified carrying a homozygous missense variant in COX18, associated with neonatal encephalo-cardiomyopathy and axonal sensory neuropathy. Here, we describe a 40-year-old patient, asymptomatic until 7 months of age, who presented with progressive muscle weakness resembling spinal muscle atrophy type-2, associated with oculofacial apraxia and dysarthric speech. Electrophysiology analysis highlighted a severe sensory-motor neuropathy. Muscle biopsy showed striking and diffuse decreases of COX staining and a substantial reduction of CIV activity. Muscle biopsy showed no ragged-red fibers, although ultrastructural mitochondrial alterations were evident. A novel homozygous variant (c.598G>A), located in the last nucleotide of exon 3, was detected in COX18 by whole-exome sequencing, which affected the splicing donor site, as demonstrated by cDNA-seq. The patient fibroblasts express a truncated form of COX18 (COX18Δ112-240) capable of assembling CIV and CIV-involving supercomplexes. However, CIV activity was decreased. COX18 full-length (COX18-fl) overexpression partially rescued CIV activity in the patient fibroblasts. The rescue of the null CIV activity in COX18-KO-HEK293 cells by overexpressing of COX18Δ112-240 was significantly lower than in cells with COX18-fl. In addition, cox-18 downregulation in C. elegans resulted in slow growth and, diminished reduced motility phenotypes and as well as severe fragmentation of the mitochondrial network. Our case expands the phenotypes associated with COX18 variants and supports the pathogenic role of COX18 as the cause of a severe encephaloneuropathy syndromeThe authors acknowledge the patient and his family, as well as the patient association ASENSE for all the support to this work. We also acknowledge the facilities and scientific and technical assistance of CITIUS (University of Seville) and the Biomolecular Mass Spectrometry Service of the Pablo de Olavide University. This work was supported in part by the Instituto de Salud Carlos III (FIS PI19-01497 to C. Paradas), Consejería de Salud y Familia, Junta de Andalucía and Programa Operativo Fondo Social Europeo de Andalucía 2014–2020 (RH0046-2020 to G.C) and Consejería de Salud y Consumo, Junta de Andalucía and Programa Nicolas Monarde (C1-0003-2022 to E.S-M). We also acknowledge the FP7 WeNMR (project# 261572), H2020 West-Life (project# 675858), the EOSC-hub (project# 777536) and the EGI-ACE (project# 101017567) European e-Infrastructure projects for the use of their web portals, which make use of the EGI infrastructure with the dedicated support of CESNET-MCC, INFN-LNL-2, NCG-INGRID-PT, TW-NCHC, CESGA, IFCA-LCG2, UA-BITP, TR-FC1-ULAKBIM, CSTCLOUD-EGI, IN2P3-CPPM, CIRMMP, SURFsara and NIKHEF, and the additional support of the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, Taiwan and the US Open Science Grid. This work was supported by the Spanish Government (PGC2018-096049-B-I00, FEDER/Ministerio de Ciencia e Innovación — Agencia Estatal de Investigación Grant PID2021-126663NB-I00 funded by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe), European Regional Development Fund (FEDER), Andalusian Government (BIO-198, US/JUNTA/FEDER) and the Ramón Areces Foundation (2021–2024 to I.D.-M.). Some of the authors are part of the European Research Network in Neuromuscular Diseases (EURO-NMD).Peer reviewedElsevierInstituto de Salud Carlos IIIEuropean CommissionMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Junta de AndalucíaFundación Ramón ArecesMavillard, Fabiola [0000-0002-1460-0483]Guerra-Castellano, Alejandra [0000-0001-5823-1678]Guerrero-Gómez, David [0000-0001-9403-6431]Rívas, Eloy [0000-0001-6014-8048]Cantero, Gloria [0000-0001-8159-9913]Servián Morilla, E. [0000-0002-6467-9740]Folland, Chiara [0000-0002-6346-4828]Ravenscroft, Gianina [0000-0003-3634-211X]Martín, Miguel A. [0000-0003-4741-772X]Miranda-Vizuete, Antonio [0000-0002-6856-5396]Cabrera-Serrano, Macarena [0000-0003-3109-6095]Díaz-Moreno, Irene [0000-0002-5318-7644]Paradas-López, Carmen [0000-0002-6917-2236]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/datasethttp://purl.org/coar/resource_type/c_ddb1Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/395317reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PGC2018-096049-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-126663NB-I00https://doi.org/10.1016/j.bbadis.2024.167330Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3953172026-05-22T06:33:51Z
score 15,811543

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