Original title: ASM Variants in the Spotlight: A Structure-Based Atlas for Unraveling Pathogenic Mechanisms in Lysosomal Acid Sphingomyelinase
Authors: Simone Scrima,Matteo Lambrughi,Matteo Tiberti,Elisa Fadda,Elena Papaleo
This article explores the role of lysosomal acid sphingomyelinase (ASM) in lipid metabolism and its association with a rare genetic disorder called acid sphingomyelinase deficiency. The researchers used a structure-based framework to study the functional implications of ASM variants by analyzing over 400 variants. They combined pathogenicity predictions with molecular dynamics simulations in a lysosomal membrane environment to gain insights into how these variants affect the protein’s function. The study establishes a structural atlas of missense variants of ASM, identifying variants that impact structural stability or have effects on functional sites. To validate their predictions, the researchers compared them to experimental data on residual catalytic activity in ASM variants. The findings also suggest that the data collected could be useful for identifying cases suitable for enzyme replacement therapy. Overall, this comprehensive approach enhances our understanding of ASM variants and provides valuable insights for potential therapeutic interventions.
Original article: https://www.biorxiv.org/content/10.1101/2023.11.24.568551v1