Severe defect in mitochondrial complex I assembly with mitochondrial DNA deletions in ACAD9-deficient mild myopathy
Konstantina Fragaki1,2, Annabelle Chaussenot1,2, Audrey Boutron3
1Nice Sophia Antipolis University, Institute for Research on Cancer and Aging (IRCAN), CNRS, INSERM, UMR 7284 and U1081, School of Medicine, 28 avenue de Valombrose, 06107, Nice cedex 2, France.
Insights
A novel Acyl-coenzyme A dehydrogenase 9 (ACAD9) mutation caused a severe defect in mitochondrial complex I assembly but a mild myopathy. This suggests major complex I assembly defects do not always lead to severe phenotypes.
Area of Science:
- Biochemistry
- Genetics
- Mitochondrial Biology
Background:
- Acyl-coenzyme A dehydrogenase 9 (ACAD9) is crucial for mitochondrial complex I (CI) assembly.
- ACAD9 mutations are rarely reported, typically causing severe hypertrophic cardiomyopathy or mild myopathy.
Observation:
- A novel homozygous ACAD9 mutation (c.1240C>T; p.Arg414Cys) was identified in a 34-year-old woman with non-progressive myopathy.
- The mutation resulted in a significant defect in CI assembly within the patient's muscle tissue.
Findings:
- The patient's muscle exhibited a severe defect in mitochondrial complex I assembly.
- Accumulation of mitochondrial DNA deletions confirmed the impact of CI deficiency.
Implications:
- This case challenges the assumption that severe CI assembly defects invariably lead to severe clinical phenotypes.
- Understanding factors influencing ACAD9 mutation severity is critical for diagnosing and managing mitochondrial disorders.
Introduction:
Acyl-coenzyme A dehydrogenase 9 (ACAD9) has a role in mitochondrial complex I (CI) assembly. Only a few patients who carry ACAD9 mutations have been reported. They mainly present with severe hypertrophic cardiomyopathy, although a minority have only mild isolated myopathy. Although the secondary factors influencing disease severity have not been elucidated, conservation of CI assembly and residual enzymatic activity have been suggested as explanations for the mild phenotypes associated with ACAD9 mutations.
Methods:
We report a novel homozygous ACAD9 mutation (c.1240C>T; p.Arg414Cys) in a 34-year-old woman who presented with non-progressive myopathy.
Results:
We show that this ACAD9 mutation led to a severe defect in CI assembly in the patient's muscle. Furthermore, the impact of CI deficiency is confirmed by accumulation of mitochondrial DNA deletions.
Conclusion:
Our data suggest that a major defect of CI assembly is not responsible for a severe phenotype. Muscle Nerve 55: 919-922, 2017.
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