[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-459383-105":59,"doc-detail-459383-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","biallelic-variants-in-cox18-cause-a-mitochondrial-disorder-primarily-manifesting-as-peripheral-neuropathy","Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy","","Biallelic COX18 variants are identified as a novel cause of autosomal recessive axonal Charcot–Marie–Tooth (CMT), with peripheral neuropathy as the main clinical feature. Exome sequencing identified a homozygous splice variant (c.435–6A>G) in two siblings, and external database searches revealed additional families with rare deleterious COX18 biallelic variants. Functional studies show altered splicing and a stable but defective COX18 isoform, impairing mitochondrial Complex IV assembly and activity, reducing mitochondrial membrane potential, and inducing neurodegenerative phenotypes in Drosophila.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/biallelic-variants-in-cox18-cause-a-mitochondrial-disorder-primarily-manifesting-as-peripheral-neuropathy/459383/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/biallelic-variants-in-cox18-cause-a-mitochondrial-disorder-primarily-manifesting-as-peripheral-neuropathy/459383.png","ImageObject",300,407,{"name":92,"@type":93},"Miles","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is COX18’s proposed role in mitochondrial Complex IV function?","Question",{"text":112,"@type":113},"COX18 encodes a mitochondrial Complex IV assembly factor that translocates the C-terminal tail of MTCO2 across the inner mitochondrial membrane.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were COX18 variants discovered in affected individuals?",{"text":117,"@type":113},"Exome sequencing and homozygosity mapping identified a homozygous splice variant (c.435–6A>G) in two siblings, and database queries found additional families with rare deleterious COX18 biallelic variants.",{"name":119,"@type":110,"acceptedAnswer":120},"What functional effects do the COX18 variants have?",{"text":121,"@type":113},"The splice variant drives expression of an alternative transcript lacking exon 2, producing a stable but defective COX18 isoform that disrupts Complex IV assembly and activity and reduces mitochondrial membrane potential.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},459383,1791116606,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36,"preview_page_count":4},13056703019404,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","[https://doi.org/10.1093/brain/awaf300](https://doi.org/10.1093/brain/awaf300) BRAIN 2026: 149; 178–193 | 178  \nBiallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy  \nCamila Armirola-Ricaurte,1,2,†,‡ Laura Morant,1,2,† Isabelle Adant,3,4  \nSherifa A. Hamed,5 Menelaos Pipis,6,7 Stephanie Efthymiou,6  \nSilvia Amor-Barris,1,2 Derek Atkinson,1,2,§ Liedewei Van de Vondel,8,9 Aleksandra Tomic,10,11 Sara Seneca,12 Els de Vriendt,1,2 Stephan Zuchner,13,14 Bart Ghesquiere,15,16 Michael G. Hanna,6 Henry Houlden,6 Michael P. Lunn,6 Mary M. Reilly,6 Vedrana Milic Rasic10,17 and Albena Jordanova1,2,18  \n†These authors contributed equally to this work.  \n‡Present address: Exeter Centre of Excellence for Diabetes Research (EXCEED), University of Exeter Medical School, Exeter EX1 2HZ, UK.  \n§Present address: Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.  \nDefects in mitochondrial dynamics are a common cause of Charcot–Marie–Tooth disease (CMT), whereas primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this aetiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane.  \nExome sequencing was performed in four affected individuals from three families. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model.  \nExome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435–6A>Gin COX18 in two siblings with early-onset progressive axonal sensorimotor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18 . All eight affected individuals presented with axonal CMT, and some patients also exhibited CNS symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs Complex IV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homologue in D. melanogaster resulted in signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons.  \nOur study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without CNS involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders, in addition to the role of mitochondrial Complex IV in the development of CMT. Our research has important implications for the diagnostic work-up of CMT patients.  \nReceived October 27, 2024. Revised July 03, 2025. Accepted July 13, 2025. Advance access publication August 20, 2025 © The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.  \nCOX18 is a novel cause of axonal CMT BRAIN 2026: 149; 178–193 | 179  \n1 Molecular Neurogenomics Group, VIB Center for Molecular","cbCaiqtSHraHy1sk","https://ap.wps.com/l/cbCaiqtSHraHy1sk","pdf",824718,16,"English","# Study aims and rationale\n## Genetic discovery and patient assessment\n## Functional validation in cells and model systems\n## Clinical implications","[{\"question\":\"What is COX18’s proposed role in mitochondrial Complex IV function?\",\"answer\":\"COX18 encodes a mitochondrial Complex IV assembly factor that translocates the C-terminal tail of MTCO2 across the inner mitochondrial membrane.\"},{\"question\":\"How were COX18 variants discovered in affected individuals?\",\"answer\":\"Exome sequencing and homozygosity mapping identified a homozygous splice variant (c.435–6A\\u003eG) in two siblings, and database queries found additional families with rare deleterious COX18 biallelic variants.\"},{\"question\":\"What functional effects do the COX18 variants have?\",\"answer\":\"The splice variant drives expression of an alternative transcript lacking exon 2, producing a stable but defective COX18 isoform that disrupts Complex IV assembly and activity and reduces mitochondrial membrane potential.\"}]","Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy | PDF",1790755818]