Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Alanyl-tRNA synthetase 1 (AARS1) variants are linked to recessive disorders and dominant neuropathies.
• No single variant has been previously associated with both dominant and recessive inheritance patterns.
• Understanding shared mechanisms between different inheritance patterns is crucial.

Purpose of the Study:

• To evaluate the functional consequences of all reported AARS1 missense variants in recessive diseases using a humanized yeast model.
• To assess whether specific AARS1 variants can exhibit both loss-of-function and dominant-negative effects.

Main Methods:

• Utilized a humanized yeast model to assess the functional impact of AARS1 missense variants.
• Performed yeast complementation assays to evaluate loss-of-function effects.
• Tested variants showing no growth for potential dominant-negative effects.

Main Results:

• The majority of AARS1 variants associated with recessive disease displayed variable loss-of-function effects in yeast.
• The yeast model proved reliable for testing AARS1 variant effects but can yield false negatives.
• K81T and E99G AARS1 variants demonstrated both loss-of-function and dominant-negative activities.

Conclusions:

• Certain AARS1 variants can underlie both dominant and recessive disease phenotypes.
• This finding suggests shared molecular mechanisms contributing to diverse inheritance patterns.
• The study highlights the complexity of genotype-phenotype correlations in AARS1-related disorders.