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

被引：4

作者：

Turco, Elisa Maria ^{[1
]}

Giovenale, Angela Maria Giada ^{[1
,2
]}

Sireno, Laura ^{[1
,3
]}

Mazzoni, Martina ^{[1
]}

Cammareri, Alessandra ^{[1
]}

Marchioretti, Caterina ^{[3
,4
]}

Goracci, Laura ^{[5
]}

Di Veroli, Alessandra ^{[5
]}

Marchesan, Elena ^{[6
]}

D'Andrea, Daniel ^{[7
]}

Falconieri, Antonella ^{[4
]}

Torres, Barbara ^{[8
]}

Bernardini, Laura ^{[8
]}

Magnifico, Maria Chiara ^{[9
]}

Paone, Alessio ^{[9
]}

Rinaldo, Serena ^{[9
]}

Della Monica, Matteo ^{[10
]}

D'Arrigo, Stefano ^{[11
]}

Postorivo, Diana ^{[12
]}

Nardone, Anna Maria ^{[12
]}

Zampino, Giuseppe ^{[13
,14
]}

Onesimo, Roberta ^{[13
,14
]}

Leoni, Chiara ^{[14
]}

Caicci, Federico ^{[15
]}

Raimondo, Domenico ^{[16
]}

Binda, Elena ^{[17
]}

Trobiani, Laura ^{[18
]}

De Jaco, Antonella ^{[18
,19
]}

Tata, Ada Maria ^{[18
,19
]}

Ferrari, Daniela ^{[3
]}

Cutruzzola, Francesca ^{[9
]}

Mazzoccoli, Gianluigi ^{[20
,21
]}

Ziviani, Elena ^{[6
]}

Pennuto, Maria ^{[3
,4
]}

Vescovi, Angelo Luigi ^{[1
,2
]}

Rosati, Jessica ^{[1
]}

机构：

[1] Fdn IRCCS Casa Sollievo Sofferenza, Cellular Reprogramming Unit, Viale Cappuccini, I-71013 San Giovanni Rotondo, FG, Italy

[2] Univ Milano Bicocca, Dept Biotechnol & Biosci, Piazza Sci 2, I-20126 Milan, Italy

[3] Veneto Inst Mol Med VIMM, Via Orus 2, I-35129 Padua, Italy

[4] Univ Padua, Dept Biomed Sci, Via Ugo Bassi 58-B, I-35131 Padua, Italy

[5] Univ Perugia, Dept Chem Biol & Biotechnol, Via Elce di Sotto 8, I-06123 Perugia, Italy

[6] Univ Padua, Dept Biol, Via Bassi 58-B, I-35121 Padua, Italy

[7] Nottingham Trent Univ, Interdisciplinary Biomed Res Ctr, Sch Sci & Technol, Clifton NG11 8NS, England

[8] Fdn IRCCS Casa Sollievo Sofferenza, Med Genet Unit, Viale Cappuccini, I-71013 San Giovanni Rotondo, Italy

[9] Univ Roma La Sapienza, Dept Biochem Sci A Rossi Fanelli, Ple Aldo Moro 5, I-00185 Rome, Italy

[10] AORN A Cardarelli, UOC Genet Med & Lab, Via Antonio Cardarelli 9, I-80131 Naples, Italy

[11] Fdn IRCCS Ist Neurol Carlo Besta, Dept Pediat Neurosci, Via Giovanni Celoria 11, I-20133 Milan, Italy

[12] Policlin Tor Vergata Hosp, Med Genet Lab, Viale Oxford 81, I-00133 Rome, Italy

[13] Fdn Policlin Univ Agostino Gemelli IRCCS, Rare Dis & Birth Defects Unit, Largo Agostino Gemelli 8, I-00168 Rome, Italy

[14] Univ Cattolica S Cuore, Dipartimento Sci Vita & Sanita Pubbl, Largo Francesco Vito 1, I-00168 Rome, Italy

[15] Univ Padua, Dept Biol, DiBio Imaging Facil, Via U Bassi 58-B, I-35121 Padua, Italy

[16] Univ Roma La Sapienza, Dept Mol Med, Viale Regina Elena 324, I-00161 Rome, Italy

[17] Fdn IRCCS Casa Sollievo Sofferenza, Unit Canc & Stem Cells, Viale Cappuccini, I-71013 San Giovanni Rotondo, FG, Italy

[18] Univ Roma La Sapienza, Dept Biol & Biotechnol Charles Darwin, Ple Aldo Moro 5, I-00185 Rome, Italy

[19] Univ Roma La Sapienza, Res Ctr Neurobiol Daniel Bovet, Ple Aldo Moro 5, I-00185 Rome, Italy

[20] Fdn IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Div Internal Med, Viale Cappuccini, I-71013 San Giovanni Rotondo, Italy

[21] Fdn IRCCS Casa Sollievo Sofferenza, Chronobiol Lab, Viale Cappuccini, I-71013 San Giovanni Rotondo, Italy

来源：

CELL DEATH & DISEASE | 2022年 / 13卷 / 11期

关键词：

GD3; GANGLIOSIDE; RAI1; CHOLESTEROL; EXPRESSION; MICE; MITOCHONDRIA; MECHANISMS; MUTATIONS; CHILDREN;

D O I：

10.1038/s41419-022-05410-7

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：16

共 66 条

[1] First Evidence of Smith-Magenis Syndrome in Mother and Daughter Due to a Novel RAI mutation [J].