Neonatal mild Complex IV deficiency with a fatal outcome is caused by COX15 gene mutations

Sara Seneca, Kim Vancampenhout, Joél Smet, Rudy Van Coster, L. Dom, Urielle Ullmann, Willy Lissens, Sonia Van Dooren, Mary-Louise Bonduelle, Linda De Meirleir

Research output: Chapter in Book/Report/Conference proceedingMeeting abstract (Book)

Abstract

Isolated complex IV deficiency is a frequent cause of respiratory chain impairment and mitochondrial disease. It has been shown that cytochrome C oxidase dysfunction can be can be consistent with the presence of mitochondrial DNA mutations in genes coding for structural subunits, or in one of several nuclear located assembly genes such as COX6B1, COX10, COX15, FASTKD2, LRPPRC, SCO1, SCO2, SURF1, TACO1.
The onset, nature and severity of the clinical presentation of these patients are heterogeneous.
Here, we report clinical, biochemical and genetic data of a male infant with pathogenic mutations in COX15. He was born as the 2nd child to healthy, not related parents. His older brother is healthy. The index case was hypotonic and presented with feeding difficulties, failure to thrive, psychomotor retardation, lactic acidosis and cardiomyopathy. His MRI was suggestive for Leigh Disease. The cardiomyopathy progressed rapidly and the patient died of heart failure at five months of age.
Oxidative phosphorylation (OXPHOS) enzyme activities were measured using spectrophotometrical analysis. Biochemical analysis showed a very mild decrease in COX activity present in fibroblasts and a low normal range COX activity in muscle tissue. Other respiratory chain activities were normal. Functional integrity of the five complexes was evaluated using blue native polyacrylamide gel electrophoresis (BN-PAGE) followed by in-gel activity staining in muscle tissue, and showed a decreased amount of fully assembled C I, CII, CII, and CIV and the presence of sub assembly products of C V.
Analysis of the muscle mtDNA showed no deletions or no pathogenic point mutations in MT-CO1-CO3. However, sequencing analysis of the coding exons of the COX15 genes revealed that the patient is compound heterozygous p.Ser151Ter/p.Pro302Leu. Subsequent analysis showed that the mother is heterozygous for the p.Ser151X mutation while the father is heterozygous for the p.Pro302Leu missense mutation. Although the number of reported COX15 mutant patients is limited to four, the p.Ser151X mutation was previously seen in two unrelated families with a predominant clinical presentation of cardiomyopathy. This mutation might represent a hot spot location in the COX15 gene.
Original languageGreek
Title of host publicationeuromit
Publication statusPublished - 20 Jun 2011
EventUnknown -
Duration: 20 Jun 2011 → …

Conference

ConferenceUnknown
Period20/06/11 → …

Keywords

  • COX15
  • OXPHOS deficiency
  • mitochondrial disorders
  • Complex IV

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