Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome.
Elisa Maria TurcoAngela Maria Giada GiovenaleLaura SirenoMartina MazzoniAlessandra CammareriCaterina MarchiorettiLaura GoracciAlessandra Di VeroliElena MarchesanDaniel D'AndreaAntonella FalconieriBarbara TorresLaura BernardiniMaria Chiara MagnificoAlessio PaoneSerena RinaldoMatteo 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 RosatiPublished in: Cell death & disease (2022)
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.
Keyphrases
- cell death
- cell cycle arrest
- induced apoptosis
- oxidative stress
- endoplasmic reticulum stress
- signaling pathway
- reactive oxygen species
- genome wide
- fatty acid
- endothelial cells
- case report
- copy number
- type diabetes
- poor prognosis
- high glucose
- insulin resistance
- ejection fraction
- pi k akt
- newly diagnosed
- weight loss
- risk assessment
- gene expression
- autism spectrum disorder
- body mass index
- weight gain
- depressive symptoms
- dna methylation
- cell proliferation
- bone marrow
- adipose tissue
- human health
- sleep quality
- induced pluripotent stem cells
- genome wide identification
- mesenchymal stem cells
- congenital heart disease