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.

Keywords: inherited retinal diseases; intrinsically disordered proteins; missense variants; protein structure.

Figure 1

(A) Metapredict generated plots of intrinsically disordered regions as a function of amino acid residue for ALMS1, a protein with the highest amount of disorder. (B) Overlay of pathogenic missense variants (top) and total missense variants (bottom) for ALMS1 generated from ClinVar’s data release.

Figure 2

(A) Metapredict generated plots of intrinsically disordered regions as a function of amino acid residue for RHO, a protein with the lowest amount of disorder. (B) Overlay of pathogenic missense variants (top) and total missense variants (bottom) for RHO generated from ClinVar’s data release.

Figure 3

(A) Disorder content and box plot comparisons for proteins in Groups 1–4. Disorder content is listed as a percentage in the chart and decimal in the box plot. Yellow = Group 1: over-representation of missense variants; Blue = Group 2: transmembrane proteins; Green = Group 3: internal and structural proteins of photoreceptors; Red = Group 4: secreted proteins. (B) Mean disorder in Groups 1–4.

Figure 4

Graph of disorder content versus the total number of missense variants. Yellow = Group 1: over-representation of missense variants; Blue = Group 2: transmembrane proteins; Green = Group 3: internal and structural proteins of photoreceptors; Red = Group 4: secreted proteins. The number of total missense variants obtained from gnomAD data (top panel) and ClinVar data (bottom panel).

Figure 5

Graph of disorder content with respect to % pathogenicity. Percentages are graphed. Yellow = Group 1: over-representation of missense variants; Blue = Group 2: transmembrane proteins; Green = Group 3: internal and structural proteins of photoreceptors; Red = Group 4: secreted proteins. The number of total missense variants was obtained from gnomAD data (top panel) and ClinVar data (bottom panel).