Mutation in KARS: A novel mechanism for severe anaphylaxis

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Anaphylaxis is a severe, potentially lethal allergic reaction with poorly understood molecular drivers.
• Lysyl-tRNA synthetase (LysRS) has known roles in protein synthesis and a noncanonical function in mast cell activation.

Observation:

• A patient with severe anaphylaxis to paper wasp venom presented with a mutation in the KARS gene, affecting LysRS.
• The P542R mutation alters LysRS protein localization and function.

Findings:

• The LysRS-P542R mutation leads to constitutive activation of the microphthalmia transcription factor.
• This aberrant activation enhances mast cell functions, including mediator synthesis and degranulation.
• Structural analysis provides insights into LysRS's role in mast cell activation.

Implications:

• Establishes a link between LysRS-P542R dysfunction and exacerbated mast cell activation in anaphylaxis.
• Suggests LysRS as a potential therapeutic target for severe allergic reactions.
• Highlights the importance of noncanonical protein functions in disease pathogenesis.