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A Marfan syndrome gene expression phenotype in cultured skin fibroblasts.

ABSTRACT: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms.We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR.Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 x 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater.

SUBMITTER: Yao Z

PROVIDER: S-EPMC2174953 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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A Marfan syndrome gene expression phenotype in cultured skin fibroblasts.

Yao Zizhen Z Jaeger Jochen C JC Ruzzo Walter L WL Morale Cecile Z CZ Emond Mary M Francke Uta U Milewicz Dianna M DM Schwartz Stephen M SM Mulvihill Eileen R ER

BMC genomics 20070912

<h4>Background</h4>Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms.<h4>Results</h4>We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with signific ...[more]

PMID: 17850668

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Project description:Fibroblasts (Fbs) effectively promote Schwann cells (SCs) migration, proliferation, and neurite regeneration. Whether Fbs express different motor and sensory phenotypes that regulate the cell behavior and peripheral nerve function has not been elucidated. The present study utilized the whole rat genome microarray analysis and identified a total of 121 differentially expressed genes between the primary cultured motor and sensory Fbs. The genes with high expression in sensory Fbs were related to proliferation, migration, chemotaxis, motility activation, protein maturation, defense response, immune system, taxis, and regionalization, while those with high expression in motor Fbs were related to neuron differentiation, segmentation, and pattern specification. Thus, the significant difference in the expression of some key genes was found to be associated with cell migration and proliferation, which was further validated by quantitative real-time PCR (qPCR). The cell proliferation or migration analysis revealed a higher rate of cell migration and proliferation of sensory Fbs than motor Fbs. Moreover, the downregulated expression of chemokine (C-X-C motif) ligand 10 (CXCL10) and chemokine (C-X-C motif) ligand 3 (CXCL3) suppressed the proliferation rate of sensory Fbs, while it enhanced that of the motor Fbs. However, the migration rate of both Fbs was suppressed by the downregulated expression of CXCL10 or CXCL3. Furthermore, a higher proportion of motor or sensory SCs migrated toward their respective (motor or sensory) Fbs; however, few motor or sensory SCs co-cultured with the other type of Fbs (sensory or motor, respectively), migrated toward the Fbs. The current findings indicated that Fbs expressed the distinct motor and sensory phenotypes involved in different patterns of gene expression, biological processes, and effects on SCs. Thus, this study would provide insights into the biological differences between motor and sensory Fbs, including the role in peripheral nerve regeneration.

Project description:Fibrillin-1 is a large glycoprotein encoded by the FBN1 gene in humans. It provides strength and elasticity to connective tissues and is involved in regulating the bioavailability of the growth factor TGF?. Mutations in FBN1 may be associated with depleted or abnormal adipose tissue, seen in some patients with Marfan syndrome and lipodystrophies. As this lack of adipose tissue does not result in high morbidity or mortality, it is generally under-appreciated, but is a cause of psychosocial problems particularly to young patients. We examined the role of fibrillin-1 in adipogenesis. In inbred mouse strains we found significant variation in the level of expression in the Fbn1 gene that correlated with variation in several measures of body fat, suggesting that mouse fibrillin-1 is associated with the level of fat tissue. Furthermore, we found that FBN1 mRNA was up-regulated in the adipose tissue of obese women compared to non-obese, and associated with an increase in adipocyte size. We used human mesenchymal stem cells differentiated in culture to adipocytes to show that fibrillin-1 declines after the initiation of differentiation. Gene expression results from a similar experiment (available through the FANTOM5 project) revealed that the decline in fibrillin-1 protein was paralleled by a decline in FBN1 mRNA. Examination of the FBN1 gene showed that the region commonly affected in FBN1-associated lipodystrophy is highly conserved both across the three human fibrillin genes and across genes encoding fibrillin-1 in vertebrates. These results suggest that fibrillin-1 is involved as the undifferentiated mesenchymal stem cells transition to adipogenesis but then declines as the developing adipocytes take on their final phenotype. Since the C-terminal peptide of fibrillin-1 is a glucogenic hormone, individuals with low fibrillin-1 (for example with FBN1 mutations associated with lipodystrophy) may fail to differentiate adipocytes and/or to accumulate adipocyte lipids, although this still needs to be shown experimentally.

Dataset Information

A Marfan syndrome gene expression phenotype in cultured skin fibroblasts.

Publications

A Marfan syndrome gene expression phenotype in cultured skin fibroblasts.

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