Group XVI - Proteoglycans
The FREM1 proteoglycan is present in both human and mouse and is distinct from the hylauronan-binding proteoglycans of Group 1. FREM1 lacks the EGF-like domains, IgG-like domains, and CCP-like domains present in Group 1. FREM1 also contains twelve CSPG repeats not present in Group 1. The twelve CSPG repeats along with Calx-Beta domains are characteristic of other proteins such as FREM3, FREM2, and FRAS1 involved in cellular adhesion in the extracellular matrix. Unlike other 12 CSPG-type proteins, FREM1 contains a C-type lectin domain.
FREM1 is localised mainly to developing hair follicles compared with the more widespread expression of other proteoglycans such as veriscan (Group 1) and different tissue distributions to other members of the 12 CSPG-type proteins. Mutations in FREM1 associated with loss of binding activity can result in developmental disorders. This binding activity is thought to anchor the epidermis to the basement membrane during embryonic development. This model is supported by the presence of two RGD motifs present in FREM1 for binding integrins. Mutations in FREM1 observed in humans and mice result in the blistering of the epidermis and affect development, further supporting a role for FREM1 in cell adhesion. Diseases resulting from these developmental defects such as MOTA (Manitoba-oculotrichoanal) syndrome have comparable phenotypes in mice. Characterised mutations resulting in these phenotypes are observed across multiple species and include missense mutations within the CSPG repeats, nonsense muations in CSPG repeats leading to truncation of the region including the C-type lectin domain, and splicing errors leading to exon skipping.
The C-type lectin domain of FREM1 lacks the residues for calcium ion coordination and so is unlikely to have sugar binding activity.
