Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect

Area of Science:

• Genetics and Molecular Biology
• Mitochondrial Biology
• Neuromuscular Disorders

Background:

• Mutations in the KARS gene, encoding lysyl-tRNA synthetase, are linked to Charcot-Marie-Tooth polyneuropathy, hearing loss, and visual impairment.
• The KARS gene product functions in both cytoplasmic and mitochondrial protein synthesis.

Observation:

• A 14-year-old girl presented with severe cardiomyopathy, psychomotor delay, and myopathy.
• Muscle biopsy revealed reduced cytochrome C oxidase (complex IV) and combined defects in complexes I and IV.
• Genetic analysis identified two previously unreported mutations in the KARS gene.

Findings:

• The novel KARS mutations are located in a highly conserved catalytic domain region.
• These variants significantly impact KARS protein stability, confirmed by structural analysis.
• The identified mutations provide a molecular basis for the patient's complex phenotype.

Implications:

• This study broadens the clinical spectrum associated with KARS mutations, including severe cardiomyopathy and mitochondrial dysfunction.
• It highlights the critical role of mitochondrial aminoacyl-tRNA synthetases (mt-ARSs) in human health.
• Further research into the diverse functions of mt-ARSs is warranted to understand their full clinical relevance.