Missense mutations in intrinsically disordered protein regions link pathogenicity and phase separation.

Scientists studied how genetic changes affect proteins that can form separate compartments in cells (called phase separation). They found that proteins involved in this process are more often linked to diseases like autism. Harmful genetic changes were three times more common in these special protein regions. This research could help doctors better understand which genetic differences actually cause health problems versus those that are harmless.

This computational study examined the relationship between genetic mutations, protein phase separation, and disease pathogenicity, with particular relevance to autism spectrum disorder. Researchers analyzed disease-associated proteins and found that those involved in phase separation (a cellular process where proteins form distinct compartments) are more commonly linked to diseases including autism. Pathogenic mutations were three times more likely to occur in phase-separating protein regions compared to other disordered regions. Specific amino acid substitutions showed varying pathogenicity levels, with arginine and aromatic amino acid changes being most harmful.

The findings suggest that understanding phase separation behavior could improve prediction of whether genetic variants cause disease.

This research may improve genetic variant interpretation by considering phase separation properties. The findings could help clinicians better assess pathogenicity of missense mutations, particularly in autism-related genes. However, experimental validation is needed before clinical implementation of these predictive approaches.

This is a computational prediction study without experimental validation. Sample sizes and specific methodologies are not reported in the abstract. The predictive models' accuracy for clinical application remains unclear, and findings require validation through functional studies.

The impact of missense genetic variations on protein function is often enigmatic, especially for mutations that map to intrinsically disordered regions (IDRs). Given the functional importance of phase separation of IDRs, it has been proposed that mutations that modulate phase separation might preferentially lead to disease. To examine this idea, we used the robust predictability of phase-separating (PS) IDRs and annotation of disease-associated proteins and mutations to map the correlation between disease and phase separation. Consistent with previous work linking phase separation to cancer and autism spectrum disorder, we find a higher prevalence of predicted phase separation behavior in disease-associated proteins than typical for human proteins.

We map the prevalence of phase separation across a wide range of diseases, finding that many, but not all, show an enrichment of phase separation in the proteins associated with them. Strikingly, the pathogenic mutation rate in predicted PS IDRs was elevated threefold relative to IDRs not predicted to phase separate. Substitutions involving arginine and the aromatic types were among the most pathogenic for PS IDRs, whereas substitutions involving serine, threonine, and alanine were the most benign. We applied these trends to mutations of uncertain clinical significance and predict that half found in PS IDRs are likely pathogenic.

We find that phosphorylation sites were enriched in PS IDRs when compared with other protein regions, though mutations at such sites were mostly benign. Pathogenicity was highest for mutations in predicted PS IDRs when also found in a short linear motif, known mediators of protein-protein interactions.