title: Early senescence in heterozygous ABCA1 mutation skin fibroblasts: a gene dosage effect beyond HDL deficiency?
abstract: OBJECTIVE
  Homozygous ABCA1 gene mutation causes Tangier disease (TD). The effects reported in heterozygous state regard plasma HDL, cell cholesterol efflux and coronary artery disease. We investigated whether in vitro replicative skin fibroblast senescence shown in TD proband (Hom), his father (Het), and in a healthy control might be induced in a "gene-dosage way".
  
  
  METHODS
  Senescence was evaluated by staining test for β-Galactosidase and telomere length (TL) on fibroblast DNA at different replicative stages. ABCG1 and LDLR (low density lipoprotein receptor) gene expression was also evaluated.
  
  
  RESULTS
  Hom cells showed early senescent morphology and reduced growth at all passages in vitro. The cell positive percentage for β-Galactosidase test was highly increased in Hom compared to Het cells at late replicative status (66.1% vs 41.3% respectively). TL was significantly shorter at high stage either in Hom (p<0.0001) or in Het (p<0.005). At early replication cycles ABCG1 gene expression was about 3-fold higher in Hom compared to Het cells (0.44 vs 0.14 arbitrary unit).
  
  
  CONCLUSIONS
  ABCA1 gene mutation may have "gene-dosage way" effect on in vitro fibroblast senescence. Furthermore, increased ABCG1 and LDLR gene expression could highlight a role of ABCA1 on cytoskeleton regulation associated to cell cholesterol metabolism.
authors.affiliation: CNR Institute of Clinical Physiology, Via Moruzzi n. 1, Pisa, Italy.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Puntoni
authors.affiliation: Fondazione Toscana Gabriele Monasterio, Via Moruzzi n. 1, Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Bigazzi
authors.affiliation: CNR Institute of Clinical Physiology, Via Moruzzi n. 1, Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Sabatino
authors.affiliation: Fondazione Toscana Gabriele Monasterio, Via Moruzzi n. 1, Pisa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sbrana
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Via Moruzzi n. 1, Pisa, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Musio
authors.affiliation: Fondazione Toscana Gabriele Monasterio, Via Moruzzi n. 1, Pisa, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Dal Pino
authors.affiliation: Fondazione Toscana Gabriele Monasterio, Via Moruzzi n. 1, Pisa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ragusa
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Savi n. 6, Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Corsano
authors.affiliation: Fondazione Toscana Gabriele Monasterio, Via Moruzzi n. 1, Pisa, Italy. Electronic address: tiziana.sampietro@ftgm.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sampietro
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics*; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D008076:Cholesterol, HDL / Q000172:deficiency* / Q000235:genetics; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D018628:Gene Dosage; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics*; D012867:Skin / Q000166:cytology*; D015595:Skin Aging / Q000235:genetics*; D013631:Tangier Disease / Q000235:genetics; D059505:Telomere Homeostasis / Q000235:genetics
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D008076:Cholesterol, HDL; C573412:LDLR protein, human; D011973:Receptors, LDL
keywords: ATP-binding cassette transporter A1; ATP-binding cassette transporter G1; Low density lipoprotein receptor; Tangier disease; Telomere length; β-Galactosidase