Human diseases linked to cytoplasmic aminoacyl-tRNA synthetases.

As an essential component of the translation machinery, aminoacyl-tRNA synthetases (aaRSs) are indispensable for cell viability. In complex multicellular organisms, this fundamental importance of aaRSs is further expanded by their broad regulatory functions, and reflected by their extensive human disease connections. This chapter focuses on the disease connection of the group of aaRSs supporting protein synthesis in the cytoplasm, including GlyRS and LysRS that are also used for mitochondrial translation. To date, three major disease types have been linked directly to cytoplasmic aaRSs: first, an autoimmune antisynthetase syndrome (ASS) characterized by the presence of autoantibodies targeting one of eight different aaRSs; second, a peripheral neuropathy, Charcot-Marie-Tooth disease (CMT) caused by dominant, mono-allelic mutations in six different aaRSs; and third, severe multi-organ disorders, often accompanied with developmental delays, caused by recessive, bi-allelic mutations in almost all cytoplasmic aaRSs. This chapter will cover broadly each of these types, with a lesser focus on CMT. An interesting feature of cytoplasmic aaRSs in complex organisms is the formation of a multi-synthetase complex (MSC), containing nine aaRSs and three non-enzymatic scaffold proteins. We note a general trend that MSC components are more likely to be involved in recessive diseases, whereas the freestanding aaRSs are predominantly linked to the dominant CMT disease and the autoimmune ASS. GlyRS and LysRS appear to be more susceptive to mutational impact, possibly due to their dual use for cytosolic and mitochondrial protein synthesis. Nevertheless, non-enzymatic functions of aaRSs are also linked to diseases as suggested by studies on ASS and CMT.