Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Intrinsically disordered regions (IDRs) are protein regions that are unable to fold into stable tertiary structures, enabling their involvement in key signaling and regulatory functions via dynamic interactions with diverse binding partners. An understanding of IDRs and their association with biological function may help elucidate the pathogenesis of inherited retinal diseases (IRDs). The main focus of this work was to investigate the degree of disorder in 14 proteins implicated in IRDs and their relationship with the number of pathogenic missense variants. Metapredict, an accurate, high-performance predictor that reproduces consensus disorder scores, was used to probe the degree of disorder as a function of the amino acid sequence. Publicly available data on gnomAD and ClinVar was used to analyze the number of pathogenic missense variants. We show that proteins with an over-representation of missense variation exhibit a high degree of disorder, and proteins with a high amount of disorder tolerate a higher degree of missense variation. These proteins also exhibit a lower amount of pathogenic missense variants with respect to total missense variants. These data suggest that protein function may be related to the overall level of disorder and could be used to refine variant interpretation in IRDs.

Automated summary

Intrinsically disordered regions (IDRs) are protein regions that lack stable tertiary structures and play important roles in signaling and regulation through dynamic interactions. Understanding IDRs and their association with biological function may shed light on the development of inherited retinal diseases (IRDs). This study aims to investigate the level of disorder in 14 proteins related to IRDs and its correlation with the number of pathogenic missense variants.