A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.
Eur J Hum Genet
; 31(12): 1414-1420, 2023 12.
Article
em En
| MEDLINE
| ID: mdl-37468577
ABSTRACT
Pathogenic variants impacting upon assembly of mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) predominantly result in early onset mitochondrial disorders often leading to CNS, skeletal and cardiac muscle manifestations. The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18 as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy. The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life. Serum lactate was consistently increased. Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2c.667 G > C p.(Asp223His) in COX18. Patient's muscle biopsy revealed severe and diffuse COX deficiency and striking mitochondrial abnormalities. Biochemical and enzymatic studies in patient's myoblasts and in HEK293 cells after COX18 silencing showed a severe impairment of both COX activity and assembly. The biochemical defect was partially rescued by delivery of wild-type COX18 cDNA into patient's myoblasts. Our study identifies a novel defect of COX assembly and expands the number of nuclear genes involved in a mitochondrial disorder due to isolated COX deficiency.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Deficiência de Citocromo-c Oxidase
/
Doenças Musculares
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
/
Infant
Idioma:
En
Revista:
Eur J Hum Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Itália