The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

Abstract

Several autism spectrum disorders (ASD) exome studies suggest that coding single nucleotide variants (SNVs) play an important role on ASD etiology. Usually, the pathogenic effect of missense mutations is estimated through predictors that lose accuracy for those SNVs placed in intrinsically disordered regions of protein. Here, we used bioinformatics tools to investigate the effect of mutations described in ASD published exome studies (549 mutations) in protein disorder, considering post-translational modification, PEST and Molecular Recognition Features (MoRFs) motifs. Schizophrenia and type 2 diabetes (T2D) datasets were created for comparison purposes. The frequency of mutations predicted as disordered was comparable among the three datasets (38.1% in ASD, 35.7% in schizophrenia, 46.4% in T2D). However, the frequency of SNVs predicted to lead a gain or loss of functional sites or change intrinsic disorder tendencies was higher in ASD and schizophrenia than T2D (46.9%, 36.4%, and 23.1%, respectively). The results obtained by SIFT and PolyPhen-2 indicated that 38.9% and 34.4% of the mutations predicted, respectively, as tolerated and benign showed functional alterations in disorder properties. Given the frequency of mutations placed in IDRs and their functional impact, this study suggests that alterations in intrinsic disorder properties might play a role in ASD and schizophrenia etiologies. They should be taken into consideration when researching the pathogenicity of mutations in neurodevelopmental and psychiatric diseases. Finally, mutations with functional alterations in disorder properties must be potential targets for in vitro and in vivo functional studies.

The role of protein intrinsic disorder in major psychiatric disorders

“…We recently showed that variants uncovered by ASD and SCZ exome studies placed in disordered regions may be harmful, affecting disorder properties and disorder related functional sites [Schuch et al, ]. However, our results from GWAS SNPs, did not show any of these adverse effects (Table ).…”

“…The present study also suggests the importance of including protein disorders when mutation functionality predictions are made. Although most of the known pathogenic mutations occurred in ordered regions [Vacic et al, ], the effects of mutations in disordered regions were underestimated [Schuch et al, ] and still need to be clarified. Psychiatric diseases present a high disorder content, which could be the target of pathogenic mutation, justifying the usage of intrinsic disorder properties.…”

“…The functional effect of the missense SNPs on protein disorder were predicted on: (i) disorder tendency (disorder‐to‐order transition prediction); (ii) phosphorylation sites predicted using Disphos and Nephos 2.0 programs [Iakoucheva et al, ; Blom et al, ]; (iii) ubiquitination sites predicted using the UbiPred webserver [Tung and Ho, ]; (iv) PEST motifs (ePESTfind server; Rechsteiner and Rogers, ); and (v) MoRF motifs (MoRFpred; Disfani et al, ). Further details on prediction methodology are described in Schuch et al [].…”

“…This control involves multiple regulatory mechanisms during transcription (e.g., miRNA control) and translation (e.g., ubiquitin‐proteasome‐dependent degradation; Gsponer et al, ; Babu et al, ; Vacic and Iakoucheva, ; Vacic et al, ). Missense mutations can manifest their impact and possibly cause diseases via disorder‐to‐order transitions [Hu et al, ; Vacic and Iakoucheva, ; Vacic et al, ; Schuch et al, ], since they could affect disorder‐relevant protein functions (protein–protein and protein‐ligand interactions, post‐translational modifications and macromolecular complex assembly). A high percentage of IDPs were associated with many diseases such as cancer (79%, Iakoucheva et al, ), cardiovascular diseases (57%; Cheng et al, ), and neurodegenerative diseases (about 80%, Raychaudhuri et al, ), resulting in the “disorder in disorder” (D 2 ) concept [Uversky et al, ].…”

Cryptic genetic variations of alanine:glyoxylate aminotransferase shape its fitness and dynamics

“…From an evolutionary point of view, the fate of a protein would then not only depend on the generation of partially-folded intermediates, but also from the equilibrium between "functional" or "potentially noxious" native conformers, which in turn might be determined by surface residues whose importance has been underestimated in classical biochemical and protein folding studies. In this regard, a growing number of reports underline that natural polymorphisms, including those related to IDRs, as key contributors to human diseases (38,39), and that single amino acid changes common in human population more likely affect binding interfaces with other proteins or nucleic acids (40).…”