The Fras1/Frem Family of Extracellular Matrix Proteins: Structure, Function, and Association with Fraser Syndrome and the MouseblebPhenotype

Abstract

Fras1 and the structurally related proteins Frem1, Frem2, and Frem3, comprise a novel family of extracellular matrix proteins, which localize in a similar fashion underneath the lamina densa of epithelial basement membranes. They are involved in the structural adhesion of the skin epithelium to its underlying mesenchyme. Deficiency in the individual murine Fras1/Frem genes gives rise to the bleb phenotype, which is equivalent to the human hereditary disorder Fraser syndrome, characterized by cryptophthalmos (hidden eyes), embryonic skin blistering, renal agenesis, and syndactyly. Recent studies revealed a functional cooperation between the Fras1/Frem gene products, in which Fras1, Frem1 and Frem2 are simultaneously stabilized at the lowermost region of the basement membrane by forming a macromolecular ternary complex. Loss of any of these proteins results in the collapse of the protein assembly, thus providing a molecular explanation for the highly similar phenotypic defects displayed by the respective mutant mice. Here, we summarize the current knowledge regarding the structure, function, and interplay between the proteins of the Fras1/Frem family and further propose a possible scenario for the evolution of the corresponding genes.

PDGFRβ regulates craniofacial development through homodimers and functional heterodimers with PDGFRα

“…Fras1, Frem1, and Frem2 have been shown to form a physical complex that is essential for the basement membrane stabilization of each protein (Kiyozumi et al 2006). As such, null mouse models of each of these family members share a subset of phenotypes that includes subepidermal blebbing, cryptophthalmos, syndactyly, and renal dysgenesis (Petrou et al 2008). Individual mutants exhibit additional phenotypes that are also observed in Pdgfra-null embryos, such as craniofacial skeletal defects (Fras1, Frem1, and Frem2), hemorrhaging (Fras1 and Frem2), cardiac septal malformations (Frem2), abnormalities in neural tube development (Frem2), abnormal sternum and rib morphology (Fras1), and pigmentation defects (Frem2) Jadeja et al 2005;Timmer et al 2005;Slavotinek et al 2011;Vissers et al 2011;Miller et al 2013).…”

Development of Monoclonal Antibodies to Interrogate Functional Domains and Isoforms of FREM1 Protein

“…By formation of a complex with FRAS1 and FREM2, FREM1 plays a role in dermal-epithermal adhesion prior to the expression of more permanent matrix proteins such as collagen during embryonic development. (2)(3)(4)(5)(6) Developmental consequences of FREM1 aberration include congenital disorders such as Manitoba-oculo-tricho-anal (MOTA) syndrome (MIM 248450) (7) and bifid nose, renal agenesis, and anorectic malformations (BNAR) syndrome (MIM 608980). (8) A splice variant of FREM1 has been found to influence cell survival and inflammation response.…”

Identification of FRAS1 as a human endometrial carcinoma-derived protein in serum of xenograft model

“…It is encoded by the FRAS1 (Fraser syndrome 1) gene, of which mutations are observed to cause Fraser syndrome [15]. Recent studies revealed a functional cooperation between the FRAS1/Frem gene products, in which FRAS1, Frem1 and Frem2 are simultaneously stabilized at the lowermost region of the basement membrane by forming a macromolecular ternary complex [16].…”