Alternative titles; symbols
HGNC Approved Gene Symbol: FREM1
SNOMEDCT: 703539006, 717940006;
Cytogenetic location: 9p22.3 Genomic coordinates (GRCh38) : 9:14,737,152-14,910,995 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p22.3 | Bifid nose with or without anorectal and renal anomalies | 608980 | Autosomal recessive | 3 |
| Manitoba oculotrichoanal syndrome | 248450 | Autosomal recessive | 3 | |
| Trigonocephaly 2 | 614485 | Autosomal dominant | 3 |
Smyth et al. (2004) cloned the mouse Frem1 gene, which encodes a deduced 2,191-amino acid protein. By searching sequence databases, they identified human FREM1. The mouse and human FREM1 proteins contain an N-terminal signal peptide, 12 chondroitin sulfate proteoglycan (CSPG; see 118661) repeats, a calcium-binding loop similar to those of sodium-calcium exchangers (see 182305), and a C-terminal C-type lectin (see 605999) domain. FREM1 also has sites for N- and O-glycosylation. FREM1 shares significant similarity with FRAS1 (607830), particularly through the CSPG repeats, but FREM1 lacks additional domains found in FRAS1. In situ hybridization and immunohistochemical analysis detected wide Frem1 expression during mouse embryonic development in the dermis and in a number of differentiating epidermal structures, such as mammary and meibomian glands, teeth, and hair follicles. Expression appeared in regions of epithelial-mesenchymal interaction and epidermal remodeling.
Alazami et al. (2009) assayed Frem1 expression in mouse embryos and found strong and specific staining in the snout as well as in the midline where the 2 medial nasal processes fuse. In situ hybridization revealed that Frem1 expression in the nose was primarily in the epithelial-mesenchymal transitional region at the midline. Based on these studies and the identification of mutations in the FREM1 gene in patients with bifid nose (see MOLECULAR GENETICS), Alazami et al. (2009) concluded that FREM1 plays an important role in fusion of the nasal processes during gestation.
Vissers et al. (2011) performed in situ hybridization of mouse embryos from mid to late gestation (E14.5-E16.5) and observed expression of Frem1 between the developing frontal bones in the region fated to form the posterior frontal suture. Antibody staining at P0 highlighted fibrillar pericranial expression of Frem1 overlying the developing frontal bones as well as staining in the dura mater underlying those bones. Low levels of diffuse Frem1 staining were also noted in the osteogenic precursors between the frontal bones, further suggesting a role for the protein in the development of the posterior frontal suture.
Smyth et al. (2004) determined that the mouse Frem1 gene contains 36 coding exons.
Slavotinek et al. (2011) noted that the FREM1 gene maps to chromosome 9p22.3.
Smyth et al. (2004) mapped the mouse Frem1 gene to chromosome 4.
Bifid Nose with or without Anorectal and Renal Anomalies
In affected members of 3 consanguineous families with bifid nose with or without anorectal and renal anomalies (BNAR; 608980) mapping to chromosome 9p23-p22.2, including an Egyptian Arab family originally reported by Al-Gazali et al. (2002), Alazami et al. (2009) sequenced the FREM1 gene and identified homozygosity for a 1-bp deletion and 2 missense mutations, respectively (608944.0001-608944.0003).
Brischoux-Boucher et al. (2020) performed microarray-based comparative genomic hybridization on a Turkish brother and sister with BNAR and detected a homozygous 30- to 52-kb in-frame microdeletion at 9p22.3 encompassing exons 19-30 of the FREM1 gene (608944.0010) in both sibs. PCR confirmed biparental inheritance. The brother had unilateral renal agenesis and bifid nose; the sister had only bifid nose.
Manitoba Oculotrichoanal Syndrome
In 8 patients from 5 families with Manitoba oculotrichoanal syndrome (MOTA; 248450), Slavotinek et al. (2011) identified homozygous or compound heterozygous mutations in the FREM1 gene (608944.0004-608944.0007, respectively).
Trigonocephaly
Vissers et al. (2011) analyzed the FREM1 gene in 104 patients with nonsyndromic trigonocephaly (see TRIGNO2; 614485) and identified missense mutations in 3 patients (608944.0008 and 608944.0009) that were not found in control chromosomes.
Smyth et al. (2004) determined that the mouse Frem1 gene is mutated in the spontaneous 'head blebs' (heb) mutation and in the N-ethyl-N-nitrosourea-induced 'bat' mutation. Both mutations cause a truncation of the Frem1 protein and result in blebbing diseases similar to Fraser syndrome (219000) and dystrophic epidermolysis bullosa (DEB; 131750) in human. Heb homozygous fetuses are characterized by cryptophthalmos and blebs restricted to the head, with the epidermis apparently normal after birth. Smyth et al. (2004) found that homozygous bat mice displayed embryonic blebbing from about 13.5 days postcoitum that invariably affected the developing eyes. Adult bat homozygotes also displayed cryptophthalmos, and about 20% had unilateral renal agenesis, which is not seen in heb homozygotes. The epidermis of bat embryos separated from the dermis below the level of the lamina densa in a manner analogous to that observed in patients with DEB. Smyth et al. (2004) concluded that Frem1 is required for epidermal adhesion during embryonic development.
Kiyozumi et al. (2006) found that Frem1-knockout mice had reduced localization of Fras1 and Frem2 (608945) to the epidermal basement membrane. Similarly, Frem2-mutant 'myelencephalic blebs' (my) mice showed depletion of Frem2, as well as Fras1 and Frem1, at the basement membrane. When coexpressed and secreted in transfected cells, Fras1, Frem1, and Frem2 formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane was due to complex formation. Kiyozumi et al. (2006) suggested that coordinated assembly of the 3 Fraser syndrome-associated proteins at the basement membrane is instrumental in epidermal-dermal interactions during morphogenetic processes.
Slavotinek et al. (2011) examined Frem1-mutant mice and identified a small but statistically significant proportion of homozygous Frem1 bat/bat mutant animals with anal prolapse, which was not observed in heterozygous or wildtype littermates. Histologic analysis revealed protrusion of the rectal epithelia and an immune infiltrate in exposed tissue, but not in internal mucosa. The musculature of the anal sphincter was present but misplaced; gross malformations in rectal musculature were not apparent. Examination of Frem1-mutant eyes at birth showed that although the majority of animals presented with frank cryptophthalmos, a subset exhibited defects strikingly similar to the eyelid coloboma seen in MOTA, seemingly affecting only 1 part of the eyelid. Histologic analysis demonstrated that these defects were associated with a number of ocular malformations including failure of eyelid formation, defects in the formation of the conjunctiva, and absence of corneal epithelium leading to fibrosis. Morphologic analysis of craniofacial shape in Frem1-deficient mice showed that homozygous mutants had reduced snout length compared to controls, and also had significantly shorter philtrum-columella height, greater intercanthal distance, and greater midface asymmetry compared to heterozygotes.
Vissers et al. (2011) studied C57BL/6J mice carrying the ENU-generated Frem1(bat) mutation, which is thought to represent a hypomorphic allele rather than a null allele. Morphometric analysis of skulls from homozygous and heterozygous mutant mice demonstrated craniofacial malformations consistent with the craniofacial features seen in the 9p22 deletion syndrome (158170), in particular metopic craniosynostosis (614485) and midface asymmetry and/or hypoplasia. The penetrance of the phenotypes in mice correlated to mutant gene dosage.
Jordan et al. (2018) dissected the diaphragms of E16.5 Frem1-deficient (eyes2/eyes2) mice on an inbred B6Brd/129S6 background and observed that development of sac hernias is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm.
In affected members of a consanguineous Egyptian Arab family with bifid nose with or without anorectal and renal anomalies (BNAR; 608980), originally reported by Al-Gazali et al. (2002), Alazami et al. (2009) identified homozygosity for a 1-bp deletion (2721delG) in exon 16 of the FREM1 gene, predicted to cause a frameshift at amino acid 908 and result in premature termination 17 residues downstream.
In affected members of a consanguineous Afghan family with bifid nose with or without anorectal and renal anomalies (BNAR; 608980), Alazami et al. (2009) identified homozygosity for a 1945C-T transition in exon 11 of the FREM1 gene, resulting in an arg649-to-trp (R649W) substitution at a highly conserved residue. The mutation was not found in 121 Afghan or 97 Indian subcontinental controls.
In affected members of a consanguineous Pakistani family with bifid nose with or without anorectal and renal anomalies (BNAR; 608980), Alazami et al. (2009) identified homozygosity for a 4318G-A transition in exon 24 of the FREM1 gene, resulting in a gly1440-to-ser (G1440S) substitution at a highly conserved residue. The mutation was not found in 97 Indian subcontinental or 121 Afghan controls.
In a male patient from an Oji-Cree family with Manitoba oculotrichoanal syndrome (MOTA; 248450), and 2 patients with MOTA from an unrelated Cree/Ojibway kindred, previously described by Li et al. (2007), Slavotinek et al. (2011) identified homozygosity for a 60.1-kb deletion (chr9:14,780,425-14,840,536) involving exons 8 through 23 of the FREM1 gene, resulting in removal of amino acids 385 to 1327 but leaving the frame of the protein unchanged. The deletion breakpoints were mapped to 631 bp after the end of exon 7 (IVS7+631) and 1,311 bp before the start of exon 24 (IVS23-1311). In 3 affected sisters, second cousins to the male Oji-Cree patient, Slavotinek et al. (2011) identified compound heterozygosity for the 16-exon deletion and a 5556A-G transition in exon 31, located 1 bp before the last coding nucleotide and predicted to abolish the donor splice site. Analysis of cDNA from 1 of the sisters confirmed that exon 31 was spliced out of the FREM1 transcript of the non-deleted allele; however, FREM1 exon 31 was also absent from cDNA from a control fibroblast cell line. Slavotinek et al. (2011) concluded that the exon 31 sequence variant was not itself pathogenic, and stated that the second mutation in the 3 sisters remained undetected.
In a woman with bilateral eyelid coloboma and vaginal atresia (MOTA; 248450), originally reported by Fryns (2001), Slavotinek et al. (2011) identified homozygosity for a 4-bp deletion (2097delATTA) in exon 13 of the FREM1 gene, predicted to cause a frameshift and premature termination of the protein. The unaffected parents were both heterozygous for the deletion.
In a female patient with Manitoba oculotrichoanal syndrome (MOTA; 248450), originally reported by Li et al. (2007), Slavotinek et al. (2011) identified compound heterozygosity for a 3971T-G transversion in the FREM1 gene, resulting in a leu1324-to-arg (L1324R) substitution at a highly conserved residue, and a 6271G-A transition, resulting in a val209-to-ile substitution (V209I; 608944.0007) at a highly conserved residue within a motif of the C-type lectin domain. Neither mutation was found in 500 or more Caucasian control chromosomes.
For discussion of the val209-to-ile (V209I) mutation in the FREM1 gene that was found in compound heterozygous state in a patient with Manitoba oculotrichoanal syndrome (MOTA; 248450) by Slavotinek et al. (2011), see 608944.0006.
In 2 patients with trigonocephaly due to metopic craniosynostosis (TRIGNO2; 614485), Vissers et al. (2011) identified heterozygosity for a 4499A-T transversion in exon 25 of the FREM1 gene, resulting in a glu1500-to-val (E1500V) substitution at a residue within the chondroitin sulfate proteoglycan repeats. The mutation was de novo in 1 of the patients; in the other patient, who had trigonocephaly and microcephaly, the mutation was also detected in the patient's mother, who had craniofacial abnormalities including hypertelorism and upslanting palpebral fissures, and in his 2 sisters, 1 of whom displayed ptosis and hypertelorism whereas the other had only relative hypertelorism but no significant findings. The mutation was not found in 142 Caucasian control chromosomes or in 110 ethnically matched control chromosomes.
In a 4-year-old boy with nonsyndromic trigonocephaly due to metopic craniosynostosis (TRIGNO2; 614485), Vissers et al. (2011) identified heterozygosity for a 1493G-A transition in exon 9 of the FREM1 gene, resulting in an arg498-to-gln (R498Q) substitution at a highly conserved residue within the chondroitin sulfate proteoglycan repeats. The mutation was inherited from his unaffected father, but was not found in 138 Caucasian control chromosomes.
Brischoux-Boucher et al. (2020) performed microarray-based comparative genomic hybridization on a Turkish brother and sister, born of consanguineous parents, with bifid nose with or without anorectal renal anomalies (BNAR; 608980) and detected a homozygous 30- to 52-kb in-frame microdeletion encompassing exons 19-30 of the FREM1 gene (608944.0010) in both sibs. PCR confirmed biparental inheritance. The brother had unilateral renal agenesis and bifid nose; the sister had only bifid nose.
Al-Gazali, L. I., Bakir, M., Hamud, O. A., Gerami, S. An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations. Clin. Dysmorph. 11: 33-38, 2002. [PubMed: 11822703] [Full Text: https://doi.org/10.1097/00019605-200201000-00007]
Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S. FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome. Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009. [PubMed: 19732862] [Full Text: https://doi.org/10.1016/j.ajhg.2009.08.010]
Brischoux-Boucher, E., Dahlen, E., Bronier, C., Nobili, F., Marcoux, E., Alkuraya, F. S., Van Maldergem, L. Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition. (Letter) Clin. Genet. 98: 515-516, 2020. [PubMed: 32926405] [Full Text: https://doi.org/10.1111/cge.13821]
Fryns, J. P. Micro-ablepharon of the upper eyelids and vaginal atresia. Genet. Counsel. 12: 101-102, 2001. [PubMed: 11332973]
Jordan, V. K., Beck, T. F., Hernandez-Garcia, A., Kundert, P. N., Kim, B.-J., Jhangiani, S. N., Gambin, T., Starkovich, M., Punetha, J., Paine, I. S., Posey, J. E., Li, A. H., and 11 others. The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia. Hum. Molec. Genet. 27: 2064-2075, 2018. [PubMed: 29618029] [Full Text: https://doi.org/10.1093/hmg/ddy110]
Kiyozumi, D., Sugimoto, N., Sekiguchi, K. Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects. Proc. Nat. Acad. Sci. 103: 11981-11986, 2006. [PubMed: 16880404] [Full Text: https://doi.org/10.1073/pnas.0601011103]
Li, C., Marles, S. L., Greenberg, C. R., Chodirker, B. N., van de Kamp, J., Slavotinek, A., Chudley, A. E. Manitoba oculotrichoanal (MOTA) syndrome: report of eight new cases. Am. J. Med. Genet. 143A: 853-857, 2007. [PubMed: 17352387] [Full Text: https://doi.org/10.1002/ajmg.a.31446]
Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. J. Med. Genet. 48: 375-382, 2011. [PubMed: 21507892] [Full Text: https://doi.org/10.1136/jmg.2011.089631]
Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J. The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis. Proc. Nat. Acad. Sci. 101: 13560-13565, 2004. [PubMed: 15345741] [Full Text: https://doi.org/10.1073/pnas.0402760101]
Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others. Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. PLoS Genet. 7: e1002278, 2011. Note: Electronic Article. [PubMed: 21931569] [Full Text: https://doi.org/10.1371/journal.pgen.1002278]