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          Institute: MPI für molekulare Genetik     Collection: Research Group Development and Disease     Display Documents

ID: 538381.0, MPI für molekulare Genetik / Research Group Development and Disease
Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity.
Authors:Horbelt, D.; Guo, G.; Robinson, P. N.; Knaus, P.
Date of Publication (YYYY-MM-DD):2010-12-15
Title of Journal:Journal of Cell Science
Journal Abbrev.:J Cell Sci
Issue / Number:Pt 24
Start Page:4340
End Page:4350
Review Status:not specified
Audience:Experts Only
Abstract / Description:Mutations in the gene encoding transforming growth factor-beta receptor type II (TGFBR2) have been described in patients with Loeys-Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). Here, we present a comprehensive and quantitative analysis of TGFBR2 expression, turnover and TGF-beta-induced Smad and ERK signaling activity for nine mutations identified in patients with LDS, MFS2 and TAAD. The mutations had different effects on protein stability, internalization and signaling. A dominant-negative effect was demonstrated for mutations associated with LDS and MFS2. No mutation showed evidence of an immediate cell-autonomous paradoxical activation of TGF-beta signaling. There were no cell biological differences between mutations described in patients with LDS and MFS2. By contrast, R460C, which has been found in familial TAAD but not in MFS2 or LDS, showed a less-severe dominant-negative effect and retained residual Smad phosphorylation and transcriptional activity. TAAD is characterized primarily by thoracic aortic aneurysms or dissections. By contrast, MFS2 is characterized by numerous skeletal abnormalities, and patients with LDS additionally can display craniofacial and other abnormalities. Therefore, our findings suggest that the balance between defects in Smad and ERK signaling might be an important determinant of phenotypic severity in disorders related to mutations in TGFBR2.
Comment of the Author/Creator:Author for correspondence:
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Institute for Chemistry-Biochemistry, Freie Universität Berlin, Berlin, 14195, Germany;
2.Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, 13353, Germany;
3.Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, 13353, Germany;
4.Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, 13353, Germany.
Identifiers:ISSN:0021-9533 [ID No:1]
URL: [ID No:2]
DOI:10.1242/jcs.074773 [ID No:3]
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