Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy

Xu, Hong‐Liang; Ji, Tuo; Lian, Yajun; Wang, Shuya; Chen, Xin; Li, Shuang; Yi, Yin; Dong, Xiubing

doi:10.1007/s00439-019-02026-4

Cited by 13 publications

(9 citation statements)

References 28 publications

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“…Exome sequencing revealed two compound heterozygous variants of the COX20 gene (c.222G > T and c.41A > G) that co-segregated with the disorder in both patients. The same variants were recently reported in a patient with ataxia and muscle hypotonia ( 15 ). The asymptomatic parents and sister of the patients were heterozygous carriers, following the characteristics of family segregation ( Figure 1B ).…”

Section: Resultssupporting

confidence: 79%

“…This variant was predicted to be benign by SIFT (predicted score: 0.135, tolerant), Polyphen-2 (HDIV: 0.005, HVAR: 0.018, both benign), MutationTaster2 (predicted score: 0.831285, disease-causing), and MutPred (predicted score: 0.149). The mutation c.41A > G ( 14 , 15 , 20 ) was classified as likely pathogenic according to the ACMG standards and guidelines (likely pathogenic = PS1 + PS3 + PM2 + PM3). In addition, genetic tests for SCA1, 2, 3, 6, 7, 12, and 17, and dentatorubral-pallidoluysian atrophy (DRPLA) of CAG repeat expansion were negative.…”

Section: Resultsmentioning

confidence: 99%

“…Mitochondria were isolated from fibroblasts based on a published protocol ( 15 ) and dissolved in 250 mM mannitol and 5 mM HEPES adjusted to pH 7.4. The samples were subjected to three freeze/thaw cycles prior to enzyme assays.…”

Section: Methodsmentioning

confidence: 99%

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

Guo

Zhang

et al. 2022

Front. Neurol.

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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.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

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

Guo

Zhang

et al. 2022

Front. Neurol.

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“…(d) Sensory-dominant axonal neuropathy, static encephalopathy, mild muscle weakness of bilateral legs, dysesthesia, dysarthria and intellectual disability, no cerebellar abnormality 30 …”

Section: Resultsmentioning

confidence: 99%

“…Clinical features include childhood-onset progressive cerebellar ataxia, sensory neuropathy, hypotonia, areflexia, dysarthria. The natural history of this condition is emerging recently albeit from small number of cases 27 – 30 , 83 . Interestingly, the two siblings even with similar genotypes showed some heterogeneity in clinical presentations, such as only one of them showing initial respiratory distress, which agrees with the established mechanism of respiratory chain assembly intermediate accumulation causing reduced respiratory capacity in the absence of COX20 protein as shown in HEK293 cells 84 .…”

Section: Discussionmentioning

confidence: 99%

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Chakravorty

Logan

Elson

et al. 2020

Sci Rep

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Pure sensory polyneuropathy of genetic origin is rare in childhood and hence important to document the clinical and genetic etiologies from single or multi-center studies. This study focuses on a retrospective chart-review of neurological examinations and genetic and electrodiagnostic data of confirmed sensory polyneuropathy in subjects at a tertiary-care Children’s Hospital from 2013 to 2019. Twenty subjects were identified and included. Neurological examination and electrodiagnostic testing showed gait-difficulties, absent tendon reflexes, decreased joint-position, positive Romberg’s test and large fiber sensory polyneuropathy on sensory nerve conduction studies in all patients associated with lower-extremity spasticity (6), cardiac abnormalities or cardiomyopathy (5), developmental delay (4), scoliosis (3), epilepsy (3) and hearing-difficulties (2). Confirmation of genetic diagnosis in correlation with clinical presentation was obtained in all cases (COX20 n = 2, HADHA n = 2, POLG n = 1, FXN n = 4, ATXN2 n = 3, ATM n = 3, GAN n = 2, SPG7 n = 1, ZFYVE26 n = 1, FH n = 1). Our single-center study shows genetic sensory polyneuropathies associated with progressive neurodegenerative disorders such as mitochondrial ataxia, Friedreich ataxia, spinocerebellar ataxia type 2, ataxia telangiectasia, spastic paraplegia, giant axonal neuropathy, and fumarate hydratase deficiency. We also present our cohort data in light of clinical features reported for each gene-specific disease subtype in the literature and highlight the importance of genetic testing in the relevant clinical context of electrophysiological findings of peripheral sensory polyneuropathy.

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Mutations in Assembly Factors Required for the Biogenesis of Mitochondrial Respiratory Chain

Cerqua

Buson

Trevisson

2021

Mitochondrial Diseases

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Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy

Cited by 13 publications

References 28 publications

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

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

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Mutations in Assembly Factors Required for the Biogenesis of Mitochondrial Respiratory Chain

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