Fibrillin1

Fibrillin-1 is a large extracellular glycoprotein that serves as a major structural component of microfibrils in connective tissues. It is encoded by the FBN1 gene and is widely expressed in tissues such as skin, blood vessels, lungs, sclera, and other organs requiring elastic support. Microfibrils formed by fibrillin-1 provide a scaffold for elastic fiber assembly and help maintain the integrity and resilience of the extracellular matrix. In addition to its structural role, fibrillin-1 binds latent transforming growth factor-beta (TGF-β) complexes, contributing to the regulation of TGF-β signaling in the extracellular milieu and influencing tissue development and homeostasis.

Genetics and structure: The FBN1 gene is located on chromosome 15q21.1. It encodes a large secreted glycoprotein that features numerous calcium-binding EGF-like (cbEGF) domains and other domains that mediate microfibril assembly. Fibrillin-1 monomers polymerize extracellularly to form beaded microfibrils, which interact with elastin to contribute to elastic fiber networks. The N- and C-terminal regions and propeptides participate in multimerization and proper assembly of the microfibril network.

Clinical significance: Mutations in FBN1 are associated with Marfan syndrome, an autosomal dominant connective tissue disorder characterized by tall stature with long limbs, skeletal deformities, ectopia lentis (lens dislocation), and progressive aortic root dilation with risk of dissection. The clinical spectrum is broad and includes related Marfan syndrome–overlap conditions with variable expressivity. Pathogenic variants can be missense, splicing, or truncating, often affecting domains critical for microfibril assembly and TGF-β regulation.

Therapeutic implications: Management focuses on surveillance of cardiovascular and ocular manifestations and may include medications that modulate TGF-β signaling, such as angiotensin receptor blockers, in addition to standard cardiovascular care.