FREM1 encodes a basement membrane protein which forms a ternary complex with the FRAS1 and FREM2 proteins. FREM1 is required for epidermal adhesion during embryonic development and is thought to be involved in craniofacial and renal development. The latter protein is composed of many functional domains, including a conserved signal sequence, a CALX-b calcium-binding loop, 12 chondroitin sulfate proteoglycan (CSPG) elements, and a C-terminal lectin Type C domain. Four isoforms of the FREM1 protein were identified.
The FREM1 gene contains 39 exons and spans over 176 kb. Mutations in FREM1 have been identified in three disorders: BNAR syndrome, trigonocephaly and Manitoba-Oculo-Tricho-Anal (MOTA) syndrome, which is characterized by a bifid or broad nasal tip, eye colobomas, cryptophthalmos and anophthalmia/microphthalmia and anal stenosis. Many types of mutations were found to cause the abovementioned disorders; examples include: deletions (1-bp del, 2721G and 4-bp del, 2097ATTA) as well as missense mutations (G1440S).
[See: UAE > Alazami et al., 2009].
Alazami et al. (2009) followed up on a consanguineous family of an Egyptian origin in which four siblings had bifid nose associated with anorectal and renal abnormalities (BNAR). Only three sibs survived. The causative mutation was a homozygous single base pair deletion in exon 17 of FREM1 (c.2721delG), which was predicted to cause a frameshift at amino acid 908 and a premature truncation 17 residues downstream (p.V908SfsX17) within the CSPG conserved domains.