Polyamine dysregulation converges with RASopathies on RAS/MAPK and sensory processing phenotypes in Drosophila

RASopathies are developmental conditions associated with cognitive and sensory processing impairments. They are caused by pathogenic variants in genes that result in overactivation of the RAS/MAPK signaling pathway. Genes linked to this pathway have been reported to be enriched among Drosophila models with habituation deficits, a behavioral phenotype reflecting sensory filtering. To identify hidden RASopathies - monogenic disorders that converge on RAS/MAPK overactivation without being classically linked to the pathway - we generated 89 and screened 41 viable habituation-deficient Drosophila RNAi models for RAS/MAPK overactivation, measured as an increased phosphorylated ERK to ERK ratio. This screen identified Sms, the ortholog of human spermine synthase (SMS), implicated in Snyder-Robinson syndrome. RAS/MAPK overactivation along with hyperreactivity and habituation impairments are confirmed in a full loss-of-function mutant. A RNAi screen targeting polyamine pathway genes identified Sat (human SAT1/2, SATL1) to reproduce these phenotypes. Knockdown of Sms or Sat in GABAergic neurons impaired habituation, implicating polyamine metabolism in inhibitory circuit function. These findings reveal previously unrecognized convergence between polyamine dysregulation and RASopathies, suggesting shared therapeutic opportunities through modulation of either pathway. SUMMARY STATEMENTUsing Drosophila, we uncovered polyamine metabolism genes, Sms and Sat, as modulators of RAS/MAPK and sensory processing, revealing a shared mechanism between polyaminopathies and RASopathies that may inform unified therapies.