Mutations in Fibrillin-1 Cause Congenital Scleroderma: Stiff Skin Syndrome

Loeys, Bart; Gerber, Elizabeth E.; Riegert–Johnson, Douglas L.; Iqbal, Saba; Whiteman, Pat; McConnell, Vivienne; Chillakuri, Chandramouli; Macaya, Daniela; Coucke, Paul; Paepe, Anne De; Judge, Daniel P.; Wigley, Fredrick M.; Davis, Elaine C.; Mardon, Helen J.; Handford, Penny A.; Keene, Douglas R.; Sakai, Lynn Y.; Dietz, Harry C.

doi:10.1126/scitranslmed.3000488

Cited by 211 publications

(228 citation statements)

References 70 publications

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“…Fibrillin-1 fragments with SSS mutations fail to support attachment and spreading of cells that express integrins avb3 and/or a5b1, which are the integrins that were reported to bind the RGD domain in fibrillin-1 (Loeys et al 2010). In addition, mice heterozygous for an RGD to RGE encoding mutation in Fbn1, predicted to cause an obligate loss of integrin binding, recapitulate the dermal sclerosis found in patients and mice heterozygous for SSS mutations (Gerber et al 2013).…”

Section: Integrin -Fibrillin Interactions and Overactivation Of Tgf-bmentioning

confidence: 80%

“…Interestingly, a specific subset of fibrillin-1 mutations causes stiff skin syndrome (SSS), a condition characterized by perinatal onset of dense dermal fibrosis and joint contracture, in the absence of any features of MFS. Skin derived from SSS patients shows large macroaggregates of disorganized microfibrils that concentrate latent TGF-b in the dermis and increased levels of Smad2 phosphorylation, indicative of overactivation of TGF-b signaling (Loeys et al 2010).…”

Section: Integrin -Fibrillin Interactions and Overactivation Of Tgf-bmentioning

confidence: 99%

“…The current view is that the altered matrix in SSS increases integrin expression by pDCs and the local concentration and activity of TGF-b, known to induce pDCs to produce even more TGF-b. The resulting increased concentrations of profibrotic and proinflammatory cytokines in the skin provide a plausible mechanism by which point mutations in a connective tissue protein can pheno-copy autoimmune scleroderma (SSc), a condition that also shows microfibrillar macroaggregates and increased dermal concentration of TGF-b, albeit through an unknown initiating event (Loeys et al 2010). …”

Section: Integrin -Fibrillin Interactions and Overactivation Of Tgf-bmentioning

confidence: 99%

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TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Section: Integrin -Fibrillin Interactions and Overactivation Of Tgf-bmentioning

confidence: 80%

Section: Integrin -Fibrillin Interactions and Overactivation Of Tgf-bmentioning

confidence: 99%

Section: Integrin -Fibrillin Interactions and Overactivation Of Tgf-bmentioning

confidence: 99%

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TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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“…Stiff Skin syndrome (SSS), an autosomal dominant disorder, is caused by mutations affecting the RGD-containing TB4 domain of fibrillin-1 (Loeys et al 2010). SSS is characterized by thickened, hard skin.…”

Section: Marfan Syndrome and Related Disordersmentioning

confidence: 99%

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

Munger¹,

Sheppard²

2011

Cold Spring Harbor Perspectives in Biology

326

275

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The growth factor TGF-b is secreted in a latent complex consisting of three proteins: TGF-b, an inhibitor (latency-associated protein, LAP, which is derived from the TGF-b propeptide) and an ECM-binding protein (one of the latent TGF-b binding proteins, or LTBPs). LTBPs interact with fibrillins and other ECM components and thus function to localize latent TGF-b in the ECM. LAP contains an integrin-binding site (RGD), and several RGD-binding integrins are able to activate latent TGF-b through binding this site. Mutant mice defective in integrin-mediated activators, and humans and mice with fibrillin gene mutations, show the critical role of ECM and integrins in regulating TGF-b signaling.

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“…Cocultures of human primary dermal fibroblasts (FS2 cells; ref. 42) and transfected HEK293T cells were established by combining 7.5 × 10 4 of each cell type in 400 μL of complete DMEM per well of an eight-well Lab Tek II chambered slide (Nunc). Cocultures were grown for 5 d, changing the medium daily.…”

Section: Methodsmentioning

confidence: 99%

C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43

Jensen

Aspinall

Handford

2014

Proc. Natl. Acad. Sci. U.S.A.

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Fibrillin microfibrils are 10-12 nm diameter, extracellular matrix assemblies that provide dynamic tissues of metazoan species with many of their biomechanical properties as well as sequestering growth factors and cytokines. Assembly of fibrillin monomers into microfibrils is thought to occur at the cell surface, with initial steps including proprotein processing, multimerization driven by the C terminus, and the head-to-tail alignment of adjacent molecules. At present the mechanisms that regulate microfibril assembly are still to be elucidated. We have used structure-informed protein engineering to create a recombinant, GFP-tagged version of fibrillin-1 (GFP-Fbn) to study this process. Using HEK293T cells transiently transfected with GFP-Fbn constructs, we show that (i) the C-terminal propeptide is an essential requirement for the secretion of fulllength fibrillin-1 from cells; (ii) failure to cleave off the C-terminal propeptide blocks the assembly of fibrillin-1 into microfibrils produced by dermal fibroblasts; and (iii) the requirement of the propeptide for secretion is linked to the presence of domains cbEGF41-43, because either deletion or exchange of domains in this region leads to cellular retention. Collectively, these data suggest a mechanism in which the propeptide blocks a key site at the C terminus to prevent premature microfibril assembly.

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Mutations in Fibrillin-1 Cause Congenital Scleroderma: Stiff Skin Syndrome

Cited by 211 publications

References 70 publications

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43

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