Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Abstract

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.

A Comprehensive Report of Intrinsically Disordered Regions in Inherited Retinal Diseases

“…The highest number of occurrences was in the 0 to 10th disorder decile, and the lowest distribution was in the 90th to 100th disorder decile. We previously showed that proteins with a high degree of disorder tolerated the greatest amount of missense variation [ 4 ], so we plotted the percent disorder of all proteins in the RetNet Database with respect to the total number of missense variants ( Figure 2 ). Regression analysis between disorder and total missense variants showed R = 0.079 and p = 0.18, between percent disorder and percent pathogenicity showing R = 0.024 and p = 0.68, as well as between % total missense and % disorder showing R = 0.062 and p = 0.301.…”

“…The Mane Select transcript was selected for each protein. The sequences were then run through Metapredict (version 2.3) to plot the intrinsically disordered regions (IDRs) as previously described [ 4 ]. Because multiple predictors are available, consensus scores have emerged to interpret the outcomes of multiple independent disorder predictors.…”

“…Because multiple predictors are available, consensus scores have emerged to interpret the outcomes of multiple independent disorder predictors. Metapredict uses deep-learning-based predictors of consensus scores from 12 proteomes to determine IDRs [ 4 ]. We calculated the percent disorder defined as the percentage of the number of amino acids in IDRs as a fraction of the total number of amino acids in the protein.…”

“…The resource gnomAD was used to examine the number of pathogenic missense variants and total missense variants for each protein as previously described [ 4 ], and gnomAD is currently the largest and most widely accessed reference population database. It provides rapid variant analysis.…”

“…Recently, Lee et al showed that the IRD proteins that exhibit a high degree of disorder tolerate a higher degree of missense variation and that these proteins also exhibit a lower amount of pathogenic missense variants with respect to total missense variants [4]. These findings were observed in 14 genes implicated in inherited retinal diseases (IRDs), which were categorized into four groups: (1) proteins with overrepresentation of missense variants (SAMD11, ALMS1, WFS1, RP1L1, KCNV2, and ADAMTS18), (2) transmembrane transport (CNGB1, CNGA1, TRPM1, ABCA4, BEST1, and KCNV2), (3) internal or structural proteins of the photoreceptors that are essential in visual function (RHO and RPE65), and (4) secreted proteins (TIMP3 and ADAMTS18) [4]. IDRs are known to affect channel protein function [5].…”