Functional analysis of PRPS1 disease alleles reveals altered polymerization and cytoskeletal organization

Disease-associated PRPS1 variants alter phosphoribosyl pyrophosphate synthetase 1 filament abundance, length, and architecture, with polymerization strongly suppressed by elevated adenosine/S-adenosylmethionine in yeast.

• Why it matters: Overlapping neurological phenotypes from PRPS1 alleles with opposing biochemical effects suggest shared cellular processes, but how variant-driven assembly changes connect to cellular state and cytoskeleton remained unclear.
• What they did: In Saccharomyces cerevisiae and patient-derived human fibroblasts, PRPS1 functionally substituted for essential paralogs, and variant effects on polymer assembly were tested alongside metabolic-state perturbation via adenosine kinase deletion.
• The result: Polymer assembly was metabolically responsive and linked to actin organization in yeast and fibroblasts, while the D183H superactivity variant promoted aberrant cytoplasmic polymerization in human cells.