Compound Heterozygous COX20 Variants Impair the Function of Mitochondrial Complex IV to Cause a Syndrome Involving Ophthalmoplegia and Visual Failure

Abstract

The cytochrome c oxidase 20 (COX20) gene encodes a protein with a crucial role in the assembly of mitochondrial complex IV (CIV). Mutations in this gene can result in ataxia and muscle hypotonia. However, ophthalmoplegia and visual failure associated with COX20 mutation have not been examined previously. Moreover, the mechanism causing the phenotype of patients with COX20 variants to differ from that of patients with mutations in other genes impairing CIV assembly is unclear. In this investigation, the aim was to assess the relation between COX20 variants and CIV assembly. We performed detailed clinical, physical, and biochemical investigations of affected individuals. Western blotting, reverse transcription-polymerase chain reaction, and blue native-polyacrylamide gel electrophoresis were used to analyze the expression level of COX20 and oxidative phosphorylation. A Seahorse XF Cell Mito Stress Test and enzymatic activity analysis were performed to evaluate mitochondrial function. Whole-exome sequencing revealed the same compound heterozygous mutations (c.41A > G and c.222G > T, NM_198076) in COX20 in two siblings. This is the first description of ophthalmoplegia and visual failure associated with COX20 variants. In vitro analysis confirmed that the COX20 protein level was significantly decreased, impairing the assembly and activity of CIV in patients' fibroblast. Overexpression of COX20 using a transduced adenovirus partially restored the function of the patients' fibroblasts. Early-onset complex movement disorders may be closely related to COX20 variants. Our results broaden the clinical phenotypes of patients with COX20 variants showing ophthalmoplegia and visual failure. Additionally, dysfunction of COX20 protein can impair the assembly and activity of CIV.

Clinical and genetic characteristics of children with COX20-associated mitochondrial disorder: case report and literature review

“…At the age of 5, our patient presented strabismus and visual impairment. Only one publication described visual impairment in two siblings associated with the COX20 gene, who carried the compound heterozygous mutations (c.41 A > G, c.222G > T) [ 11 ]. Multiple variants have been identified as the cause of visual impairment in mitochondrial diseases.…”

“…1 ) Located within the donor splice of exon 1, the missense c.41 A > G (p.Lys14Arg) mutation may result in a 20 bp deletion. As has been proven, this variant results in aberrant splicing and the premature termination codon p.Gly8Valfs*2, which further leads to nonsense-mediated mRNA degradation by producing a shorter and more unstable transcript [ 4 , 11 ]. Located within the exon 4, the nonsense c.259 C > T (p.Gln87Ter) mutation results in premature termination of the coding protein in exon4, and the length of the missing coding protein exceeds 10% of the normal coding protein, which impairs the function of the coding protein product.…”

Comparative Analysis of Differential Cellular Transcriptome and Proteome Regulation by HIV-1 and HIV-2 Pseudovirions in the Early Phase of Infection

“…At 12 h post-transduction, HIV-1 enhanced the expression of COX20, a member of the Cytochrome C oxidase complex and an essential part of the mitochondrial respiratory chain complex IV [ 34 ]. The p2 peptide, which is released during HIV-1 uncoating in the early phase of the viral life cycle, can activate cytochrome C oxidase and increase ATP production to enhance HIV-1 reverse transcription and nuclear import [ 35 ].…”

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

“…To date, mutations in the subunits encoded by both genomes have been associated with disorder ( MT-CO1 [ 52 ], MT-CO2 [ 53 ], MT-CO3 [ 54 ], COX4I1 [ 55 ], COX4I2 [ 56 ], COX5A [ 57 ], COX6A1 [ 56 , 58 ], COX6A2 [ 56 , 59 ], COX6B1 [ 60 ], COX7A1 [ 56 ], COX7A2 [ 56 ], COX7B [ 61 ], COX8A [ 62 ], and NDUFA4 or COXFA4 [ 63 ]), while the majority of isolated COX deficiencies are caused by mutations in COX assembly factors. Specifically, disorder-causing mutations were found in genes such as SURF1 (the first identified nuclear gene encoding a factor involved in the biogenesis of COX and being mutated in the neurodegenerative Leigh’s syndrome with COX deficiency) [ 64 , 65 ]; SCO2/SCO1 (involved in mitochondrial copper pathway) [ 66 , 67 ]; COX10 and COX15 (involved in heme A biosynthesis) [ 68 , 69 , 70 ]; COX14 (or C12ORF62 ; involved in COX assembly) [ 71 ]; COX20 (or FAM36A ; involved in MT-CO2 stabilization) [ 72 ]; COA3 ( CCDC56 or MITRAC12; involved in MT-CO1 maturation) [ 73 ]; PET100 (involved in COX biogenesis) [ 74 ]; PET117 (involved in the assembly of MT-CO2) [ 75 ]; COA5 ( C2ORF64) [ 76 ]; COA6 [ 77 ]; COA7 [ 78 ]; COA8 (previously known as APOPT1 ) [ 79 ]; FASTKD2 […”