MiSynPat

MiSynPat is a web-based application and knowledgebase dedicated to human mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) and clinically relevant (disease-related) mutations. It is dedicated to a broad audience of specialists (clinicians and researchers) and of non-specialists (for instance patients and patient associations, but also anyone willing and interested) by providing a dynamic, comprehensive and ergonomic graphical user interface with two main applications:

• Database, for existing mutations (providing the exhaustive list of mutations, links to literature, information, indicating allelic compositions in patients, depicting the mutations on protein sequences, multiple sequence alignments, and 3D modeled structures)
• Web application, providing tools to visualize the impact of possible new mutation (for diagnosis) on sequence-conservation-structure interrelation of mt-aaRSs

Aminoacyl-tRNA synthetases (aaRSs) are enzymes implicated in one of the key steps of the protein biosynthesis process. They are responsible for the specific ligation of amino acids to their cognate tRNAs via a two-steps reaction (amino acid activation and transfer of the activated amino acid onto the cognate tRNA). In human mitochondria, mt-aaRSs are involved in the synthesis of 13 mt-DNA-encoded proteins, all subunits of the respiratory chain complexes, and thereby implicated in ATP (cellular energy) synthesis. Human mt-aaRSs are all encoded by nuclear genes, by a set of genes distinct from the one coding for the cytosolic aaRSs, with solely two exceptions (GlyRS and LysRS). Of note, no gene coding for the mt-GlnRS has yet been found.

Human mt-aaRSs and mitochondrial translation: Under normal conditions, mt-aaRSs participate in the synthesis of the 13 mt-DNA encoded subunits of the respiratory chain complexes, and is thus implicated in the cellular energy production in the form of ATP. RNA components (i.e. 22 tRNAs, 13 mRNAS and 2 rRNAs) for the mitochondrial translation machinery are encoded by the mitochondrial genome (mt-DNA). Conversely, all requested proteins are encoded within the nuclear genome, translated into the cytosol, and imported into the mitochondria. This is for instance the case for the 19 aaRSs of mitochondrial location. Of note, no gene coding for a human mt-GlnRS has been found so far.

The first correlation between a mutation affecting a mt-aaRS and a human disease dates back to the year 2007, when mutations within the DARS2 gene, coding for mt-AspRS, was associated with Leukoencephalopathy with Brain stem and Spinal cord involvement and Lactate elevation (LBSL). Many other mutations have been discovered since, so that nowadays 16 out of the 17 genes encoding mt-aaRSs have been reported to be impacted by pathogenic mutations. All mutations reported so-far lead to autosomal (i.e. affecting any chromosome other than a sex chromosome) recessive disorders. Patients are either compound heterozygotes (with both recessive alleles for a same gene mutated at different location) or homozygotes (with both recessive alleles for a same gene identically mutated at the same location). As new mutations are recurrently described, MiSynPat offers follow-up tools of pertinent information, allying literature and sequence-structure-conservation knowledge, so that to assist data interpretation in pursuance of reaching a lucid diagnosis.