Phase Separation Contributes to Pathogenicity for Nonsense Mediated Decay-Escaping Variant Alleles
Xu, J.; Schmidt, J.; Bozkurt-Yozgatli, T.; Egab, I.; Mestroni, L.; Taylor, M.; Posey, J. E.; Gibbs, R. A.; Boerwinkle, E.; de Vries, P. S.; Morrison, A.; Yi, S.; Shaw, C.; Carvalho, C. M. B.; Lupski, J. R.; Jagannathan, S.; Timucin, E.; Coban-Akdemir, Z.
Show abstract
Nonsense-mediated decay (NMD) as an RNA-surveillance pathway degrades transcripts with variants introducing premature termination codons (i.e., PTC-variants), yet a substantial subset of pathogenic PTC-variants downstream of the final exon-exon junction is predicted to escape NMD (NMD-escape) based on the canonical 50-bp rule. Our systematic analysis of germline pathogenic PTC-variants from ClinVar revealed 148 autosomal dominant (AD) disease genes enriched for predicted NMD-escape alleles. These genes span nonsense (N=63), -1 frameshift (N=34), and +1 frameshift (N=22) variants, with 23 genes enriched for two classes and 6 for all three. Although their loss-of-function intolerance score distributions did not differ from controls (P = 0.407), these genes exhibited significantly higher protein-protein interaction (PPI) network centrality (P < 0.05) with their NMD-escape regions enriched for PPI interfaces (P < 0.001 for -1 and nonsense) and low-complexity sequences (P < 0.03 for -1 and +1). P/LP variants also produced significantly longer mutant C-terminal tails than controls (P < 0.01), increasing potential for functional disruption. Structural modeling of altered C-terminal tails revealed recurrent gains of glycine/proline (P < 0.03) and changes in aromatic residue content consistent with altered intrinsic disorder. Integration with neurodevelopmental disorder gene sets identified 25 dosage-sensitive genes with predicted NMD-escape P/LP variants, seven (28%) encoding condensate-forming proteins. Variant-level modeling in representative genes (e.g., KAT6B) showed altered phase-separation propensity driven by truncated and/or altered intrinsically disordered regions. Overall, this study implicates condensate dysregulation as a potential downstream biophysical consequence of NMD-escape disease alleles, providing a protein-feature viewer for variant interpretation (https://github.com/schmidtjacob46/NMDesc-protein-viewer).
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