Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome

November 2022

Elisa Maria TurcoAngela Maria Giada GiovenaleLaura SirenoMartina MazzoniAlessandra CammareriCaterina MarchiorettiLaura GoracciAlessandra Di VeroliElena MarchesanDaniel D’AndreaAntonella FalconieriBarbara TorresLaura BernardiniMaria Chiara MagnificoAlessio PaoneSerena Rinaldo, Matteo Della MonicaStefano D’ArrigoDiana PostorivoAnna Maria NardoneGiuseppe ZampinoRoberta OnesimoChiara LeoniFederico CaicciDomenico RaimondoElena BindaLaura TrobianiAntonella De JacoAda Maria TataDaniela FerrariFrancesca CutruzzolàGianluigi MazzoccoliElena ZivianiMaria PennutoAngelo Luigi VescoviJessica Rosati 



Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.