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

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-10, Vol.1870 (7), p.167330, Article 167330
• Main Authors: Mavillard, Fabiola, Guerra-Castellano, Alejandra, Guerrero-Gómez, David, Rivas, Eloy, Cantero, Gloria, Servian-Morilla, Emilia, Folland, Chiara, Ravenscroft, Gianina, Martín, Miguel A., Miranda-Vizuete, Antonio, Cabrera-Serrano, Macarena, Diaz-Moreno, Irene, Paradas, Carmen
• Format: Article
• Language: English
• Subjects: Apraxias - genetics; Complex IV; COX18; Encephaloneuropathy; Female; Hereditary Sensory and Motor Neuropathy - genetics; Hereditary Sensory and Motor Neuropathy - pathology; Homozygote; Humans; Male; Missplicing; Mitochondria; Mutation; Pedigree; RNA Splicing - genetics; Supercomplex
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167330

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. •COX18 variant triggers missplicing resulting in a pathological truncated protein.•Pathogenic variant of COX18 causes SMA-like phenotype with oculofacial apraxia.•Truncated COX18 leads COX2 depletion and reduction of complex IV activity.•Pathological COX18 alters mitochondrial morphological and network.