Cell Death and Disease (Nov 2022)
Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome
- Elisa Maria Turco,
- Angela Maria Giada Giovenale,
- Laura Sireno,
- Martina Mazzoni,
- Alessandra Cammareri,
- Caterina Marchioretti,
- Laura Goracci,
- Alessandra Di Veroli,
- Elena Marchesan,
- Daniel D’Andrea,
- Antonella Falconieri,
- Barbara Torres,
- Laura Bernardini,
- Maria Chiara Magnifico,
- Alessio Paone,
- Serena Rinaldo,
- Matteo Della Monica,
- Stefano D’Arrigo,
- Diana Postorivo,
- Anna Maria Nardone,
- Giuseppe Zampino,
- Roberta Onesimo,
- Chiara Leoni,
- Federico Caicci,
- Domenico Raimondo,
- Elena Binda,
- Laura Trobiani,
- Antonella De Jaco,
- Ada Maria Tata,
- Daniela Ferrari,
- Francesca Cutruzzolà,
- Gianluigi Mazzoccoli,
- Elena Ziviani,
- Maria Pennuto,
- Angelo Luigi Vescovi,
- Jessica Rosati
Affiliations
- Elisa Maria Turco
- Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Angela Maria Giada Giovenale
- Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Laura Sireno
- Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Martina Mazzoni
- Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Alessandra Cammareri
- Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Caterina Marchioretti
- Veneto Institute of Molecular Medicine (VIMM)
- Laura Goracci
- Department of Chemistry, Biology, and Biotechnology, University of Perugia
- Alessandra Di Veroli
- Department of Chemistry, Biology, and Biotechnology, University of Perugia
- Elena Marchesan
- Department of Biology, University of Padova
- Daniel D’Andrea
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University
- Antonella Falconieri
- Department of Biomedical Sciences, University of Padova
- Barbara Torres
- Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Laura Bernardini
- Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Maria Chiara Magnifico
- Department of Biochemical Sciences, “A. Rossi Fanelli”, University of Rome “La Sapienza”
- Alessio Paone
- Department of Biochemical Sciences, “A. Rossi Fanelli”, University of Rome “La Sapienza”
- Serena Rinaldo
- Department of Biochemical Sciences, “A. Rossi Fanelli”, University of Rome “La Sapienza”
- Matteo Della Monica
- UOC Genetica Medica e di Laboratorio, AORN “A. Cardarelli”
- Stefano D’Arrigo
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta
- Diana Postorivo
- Medical Genetics Laboratory, “Policlinico Tor Vergata” Hospital
- Anna Maria Nardone
- Medical Genetics Laboratory, “Policlinico Tor Vergata” Hospital
- Giuseppe Zampino
- Rare Diseases and Birth Defects Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
- Roberta Onesimo
- Rare Diseases and Birth Defects Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
- Chiara Leoni
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del S. Cuore
- Federico Caicci
- Department of Biology, DiBio Imaging Facility, University of Padova
- Domenico Raimondo
- Department of Molecular Medicine, University of Rome “La Sapienza”
- Elena Binda
- Unit of Cancer and Stem Cells, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Laura Trobiani
- Department of Biology and Biotechnology “Charles Darwin”, University of Rome “La Sapienza”
- Antonella De Jaco
- Department of Biology and Biotechnology “Charles Darwin”, University of Rome “La Sapienza”
- Ada Maria Tata
- Department of Biology and Biotechnology “Charles Darwin”, University of Rome “La Sapienza”
- Daniela Ferrari
- Veneto Institute of Molecular Medicine (VIMM)
- Francesca Cutruzzolà
- Department of Biochemical Sciences, “A. Rossi Fanelli”, University of Rome “La Sapienza”
- Gianluigi Mazzoccoli
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza
- Elena Ziviani
- Department of Biology, University of Padova
- Maria Pennuto
- Veneto Institute of Molecular Medicine (VIMM)
- Angelo Luigi Vescovi
- Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- Jessica Rosati
- Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini
- DOI
- https://doi.org/10.1038/s41419-022-05410-7
- Journal volume & issue
-
Vol. 13,
no. 11
pp. 1 – 16
Abstract
Abstract 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.
