Dataset Information

Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.

ABSTRACT:

Background

Isolated cytochrome c oxidase (COX) deficiency is usually associated with mutations in several factors involved in the biogenesis of COX.

Methods

We describe a patient with atypical, long surviving Leigh syndrome carrying two novel mutations in the COX15 gene, which encodes an enzyme involved in the biosynthesis of heme A.

Results

Only two COX15 mutated patients, one with severe neonatal cardiomyopathy, the other with rapidly fatal Leigh syndrome, have been described to date. In contrast, our patient had a slowly progressive course with no heart involvement. COX deficiency was mild in muscle and a normal amount of fully assembled COX was present in cultured fibroblasts.

Conclusions

The clinical and biochemical phenotypes in COX15 defects are more heterogeneous than in other conditions associated with COX deficiency, such as mutations in SURF1.

SUBMITTER: Bugiani M

PROVIDER: S-EPMC1736058 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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Publications

Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.

Bugiani M M Tiranti V V Farina L L Uziel G G Zeviani M M

Journal of medical genetics 20050501 5

<h4>Background</h4>Isolated cytochrome c oxidase (COX) deficiency is usually associated with mutations in several factors involved in the biogenesis of COX.<h4>Methods</h4>We describe a patient with atypical, long surviving Leigh syndrome carrying two novel mutations in the COX15 gene, which encodes an enzyme involved in the biosynthesis of heme A.<h4>Results</h4>Only two COX15 mutated patients, one with severe neonatal cardiomyopathy, the other with rapidly fatal Leigh syndrome, have been descr ...[more]

PMID: 15863660

Similar Datasets

Project description:BackgroundLeigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear.MethodsTwo unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants.ResultsWe reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells.ConclusionOur results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.

Dataset Information

Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.

Background

Methods

Results

Conclusions

Publications

Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.

Similar Datasets

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