The role of Fras1/Frem proteins in the structure and function of basement membrane.

Basement membranes constitute architecturally complex extracellular matrix (ECM) protein networks of great structural and regulatory importance. Recently, a novel group of basement membrane proteins, Fras1 (Fraser syndrome protein (1) and the Fras1-related extracellular matrix proteins Frem1, Frem2 and Frem3, has emerged. They comprise components of the sublamina densa region and contribute to embryonic epithelial-mesenchymal integrity. Fras1/Frem share common polypeptide repetitive motifs with possible interactive and organizing functions. Mutations in genes encoding Fras1, Frem1 and Frem2 are causative for dermal-epidermal detachment in the plane of sublamina densa and have been identified in different classes of mouse bleb mutants, the murine model of human Fraser syndrome, the hallmark phenotypic characteristics of which are embryonic skin blistering, cryptophthalmos and renal agenesis. Indeed, defects in FRAS1 and FREM2 have been identified in Fraser syndrome patients. The phenotypic similarity of mouse bleb mutant strains can be attributed to the fact that Fras1, Frem1 and Frem2 have been experimentally shown to interact, forming a mutually stabilized protein complex, while Frem3, which has not yet been associated with any of the existing known mutations, operates in a more independent fashion. Fras1/Frem have been recently proposed to compensate for the activity of collagen VII, a major anchoring component of the sublamina densa, the levels of which rise only during late embryonic life. By focusing on the aforementioned data, in this review we will summarize the current knowledge about Fraser syndrome proteins and describe their contribution to basement membrane biology.