Our results establish that the PAP-related substitutions in MetRS impact the tRNA<sup>Met</sup> -aminoacylation reaction especially at the level of methionine recognition, and suggest a direct link between the loss of activity of the enzyme and the pathological disorders in PAP.
In addition, pulmonary alveolar proteinosis is associated with mutations in CSF2RA, CSF2RB, and MARS, and specific auto-inflammatory forms of chILD implicate STING and COPA disorders.
In summary, identification of a founder mutation in MARS led to the molecular definition of a specific type of PAP and will enable carrier screening in the affected community and possibly open new treatment opportunities.