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. 2017 Oct;38(10):1316-1324.
doi: 10.1002/humu.23277. Epub 2017 Jun 27.

MiSynPat: An integrated knowledge base linking clinical, genetic, and structural data for disease-causing mutations in human mitochondrial aminoacyl-tRNA synthetases

Luc Moulinier  1 , Raymond Ripp  1 , Gaston Castillo  1   2 , Olivier Poch  1 , Marie Sissler  2
Affiliations

MiSynPat: An integrated knowledge base linking clinical, genetic, and structural data for disease-causing mutations in human mitochondrial aminoacyl-tRNA synthetases

Luc Moulinier et al. Hum Mutat. 2017 Oct.

Abstract

Numerous mutations in each of the mitochondrial aminoacyl-tRNA synthetases (aaRSs) have been implicated in human diseases. The mutations are autosomal and recessive and lead mainly to neurological disorders, although with pleiotropic effects. The processes and interactions that drive the etiology of the disorders associated with mitochondrial aaRSs (mt-aaRSs) are far from understood. The complexity of the clinical, genetic, and structural data requires concerted, interdisciplinary efforts to understand the molecular biology of these disorders. Toward this goal, we designed MiSynPat, a comprehensive knowledge base together with an ergonomic Web server designed to organize and access all pertinent information (sequences, multiple sequence alignments, structures, disease descriptions, mutation characteristics, original literature) on the disease-linked human mt-aaRSs. With MiSynPat, a user can also evaluate the impact of a possible mutation on sequence-conservation-structure in order to foster the links between basic and clinical researchers and to facilitate future diagnosis. The proposed integrated view, coupled with research on disease-related mt-aaRSs, will help to reveal new functions for these enzymes and to open new vistas in the molecular biology of the cell. The purpose of MiSynPat, freely available at http://misynpat.org, is to constitute a reference and a converging resource for scientists and clinicians.

Keywords: 3D structures; aminoacyl-tRNA synthetases; disease-causing mutations; knowledge base; mitochondrial disorders; sequence alignments.

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Figures

Figure 1
Figure 1
Screen capture of the Home page. The home page provides access to all MiSynPat resources. Four main sections have been designed. The “header” section has a text search widget and access to the home page as well as to a synthetic description of the mt‐aaRSs scientific background, the contact and the help pages. The “access” section has five main entry points: All systems, Mutations Overview, Diseases, Mutations Statistics, and Bibliography. The “mutation” section gives direct access to the mutation modeling tool and the “bibliography” section provides a plot of the automatically updated cumulative number of bibliographic entries with reported cases of human mt‐aaRS disorders is shown in an automatically updated plot
Figure 2
Figure 2
Screen capture of the “All Systems” synoptic page. The page provides general overviews of the 19 interactive insets corresponding to the 19 human mt‐aaRSs. Each inset contains the ModMutGimmick with the mutations localized by lollipops, the 3D structure thumbnail, the name and length of the human mt‐aaRS, the date of the most recent update and the current number of bibliographic entries (bib. entries). The ModMutGimmick is as an interactive true‐scale graphical representation of the mt‐aaRS modular organization with colored boxes (see Supp. Table S3) indicating idiosyncratic and common functional regions and motifs. The reported mutations are schematized as follow: (i) recessive disease‐related missense mutations are indicated by green and orange lollipops for homozygous and compound heterozygous mutations, respectively, (ii) dominant mutations are indicated by cyan lollipops, and (iii) nonsense mutations are indicated by black lollipops
Figure 3
Figure 3
Screen capture of the DARS2 Integrative Analysis tab. From top to bottom, the page provides: UniProt/NCBI and MSeqDR links, the interactive ModMutGimmick with a black line indicating the compound heterozygous status of the patient, who has the R179H mutation associated with the E425X mutation, the linear sequence of the human mt‐AspRS, the JSmol 3D structure viewer window (either a crystallographic structure or a 3D model) with its control panel, the 3D Mutation toolbox to select and render the 3D model of a known disease‐related mutation or a user‐defined mutation. Upon selection of the R179H mutation in the dropdown menu, the conservation status, the relative solvent accessibility, and all known alleles with the bibliographic references are displayed. The mutated structure can be calculated and rendered by clicking on the “Generate the mutated structure” button. Finally, the same information can be obtained for a user‐defined mutation in the “Evaluate your own mutation” section
Figure 4
Figure 4
View of the DARS2 Alignment tab. Below the ModMutGimmick, the multiple sequence alignment of the mt‐AspRS sequences from bacterial, archaeal, and eukaryotic origin is visible through a sliding window. The human mt‐AspRS, highlighted in red, appears twice, at the top of the alignment and within its closest relatives. The Color Feature dropdown menu displays: (i) the conservation mode (black, gray, and light gray boxes correspond to 100% strictly conserved residues, more than 80% strictly conserved residue, and more than 60% physico‐chemically conserved residues, respectively); (ii) functional modules as shown in ModMutGimmick; (iii) PFAM domains; (iv) PhyloBlock; and (v) secondary structures. The absolute position ruler is scaled on the ModMutGimmick allowing a rapid focus to the clicked position. The “Toggle IDs” button switches between the default MiSynPat sequence name nomenclature and the UniProt/NCBI accession number. Clicking on one residue (indicated in red) of the human mt‐AspRS sequence from the alignment will automatically highlight this residue in all options of the Integrative Analysis tab
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