title: ALMS1-deficient fibroblasts over-express extra-cellular matrix components, display cell cycle delay and are resistant to apoptosis.
abstract: Alström Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions.
authors.affiliation: Department of Medical and Surgical Sciences, University of Padua, Padua, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zulato
authors.forename: Francesca
authors.initials: F
authors.lastname: Favaretto
authors.forename: Caterina
authors.initials: C
authors.lastname: Veronese
authors.forename: Stefano
authors.initials: S
authors.lastname: Campanaro
authors.forename: Jan D
authors.initials: JD
authors.lastname: Marshall
authors.forename: Sara
authors.initials: S
authors.lastname: Romano
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.forename: Gayle B
authors.initials: GB
authors.lastname: Collin
authors.forename: Barbara
authors.initials: B
authors.lastname: Zavan
authors.forename: Anna S
authors.initials: AS
authors.lastname: Belloni
authors.forename: Enrica
authors.initials: E
authors.lastname: Rampazzo
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Naggert
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abatangelo
authors.forename: Nicola
authors.initials: N
authors.lastname: Sicolo
authors.forename: Pietro
authors.initials: P
authors.lastname: Maffei
authors.forename: Gabriella
authors.initials: G
authors.lastname: Milan
authors.forename: Roberto
authors.initials: R
authors.lastname: Vettor
mesh_terms: D000328:Adult; D056769:Alstrom Syndrome / Q000235:genetics / Q000473:pathology; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D048430:Cell Shape; D048429:Cell Size; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C490729:ALMS1 protein, human; D018797:Cell Cycle Proteins; D011506:Proteins; D012333:RNA, Messenger