Abstract
Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin-1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes.
Highlights
Mutations in fibrillin-1 cause the pleiotropic features of the Marfan syndrome (MFS, OMIM#154700)
A novel mutation in fibrillin-1 demonstrates that modulation of the fibrillin microfibril scaffold can influence tissue microenvironments and result in the clinical features of Weill-Marchesani syndrome (WMS), including thick skin, short stature, and brachydactyly
Dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of Transforming Growth Factor b (TGFb) signaling in multiple tissues
Summary
Mutations in fibrillin-1 cause the pleiotropic features of the Marfan syndrome (MFS, OMIM#154700). More than a thousand different mutations in FBN1, the gene for fibrillin-1, are known to cause MFS, suggesting that the same general pathogenetic mechanisms are initiated by each of these distinct mutations. WeillMarchesani syndrome (WMS, OMIM #608328) is a rare disorder described as ‘‘opposite’’ to MFS [1]. WMS, one of several types of acromelic chondrodysplasias, is characterized by short stature, brachydactyly, thick skin, and ectopia lentis. Since the clinical features of WMS and MFS may sometimes overlap [6], it is not certain how rare mutations in FBN1 can bring about WMS instead of MFS. Additional investigations are required in order to clearly establish the role of fibrillin-1 in causing WMS
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