Armirola-Ricaurte, Camila; Morant, Laura; Adant, Isabelle; Hamed, Sherifa Ahmed; Pipis, Menelaos; Efthymiou, Stephanie; Amor-Barris, Silvia; ... Jordanova, Albena; + view all Armirola-Ricaurte, Camila; Morant, Laura; Adant, Isabelle; Hamed, Sherifa Ahmed; Pipis, Menelaos; Efthymiou, Stephanie; Amor-Barris, Silvia; Atkinson, Derek; Van de Vondel, Liedewei; Tomic, Aleksandra; Seneca, Sara; de Vriendt, Els; Zuchner, Stephan; Ghesquiere, Bart; Hanna, Michael; Houlden, Henry; Lunn, Michael P; Reilly, Mary M; Rasic, Vedrana Milic; Jordanova, Albena; - view fewer (2025) Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy. Brain , Article awaf300. 10.1093/brain/awaf300.

Preview

Text awaf300.pdf - Accepted Version Download (1MB) | Preview

Abstract

while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome 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. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensory-motor 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 central nervous system 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 CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homolog in Drosophila melanogaster displayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without central nervous system involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders and the role of mitochondrial CIV in the development of CMT. Our research has important implications for the diagnostic workup of CMT patients.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as XMLCSVJSON

Archive Staff Only

View Item