Alternative titles; symbols
HGNC Approved Gene Symbol: FOSL2
Cytogenetic location: 2p23.2 Genomic coordinates (GRCh38) : 2:28,392,858-28,417,317 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.2 | Aplasia cutis-enamel dysplasia syndrome | 620789 | Autosomal dominant | 3 |
The FOSL2 gene encodes a subunit of the activator protein-1 (AP-1) complex, a ubiquitous complex involved in cellular functions such as proliferation, apoptosis, differentiation, survival, and migration, as well as in development and immune function (summary by Cospain et al., 2022).
Using FOS (164810) as a probe to screen human cDNA libraries, Matsui et al. (1990) isolated a FRA2 cDNA. The FRA2 open reading frame encodes a 326-amino acid protein with the leucine zipper domain and C-terminal region conserved in the FOS family.
The FOS gene family consists of 4 members: FOS, FOSB (164772), FRA1 (136515), and FRA2 (Molven et al., 1996). These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (see 165160), thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. In some cases, expression of the FOS gene has also been associated with apoptotic cell death.
Bozec et al. (2008) demonstrated that the FOS-related protein FRA2 controls osteoclast survival and size. They observed that bones of Fra2-deficient newborn mice had giant osteoclasts, and signaling through leukemia-inhibitory factor (LIF; 159540) and its receptor (LIFR; 151443) was impaired. Similarly, newborn animals lacking Lif had giant osteoclasts, and Bozec et al. (2008) demonstrated that LIF is a direct transcriptional target of FRA2 and c-JUN (604641). Moreover, bones deficient in Fra2 and Lif were hypoxic and expressed increased levels of hypoxia-induced factor 1-alpha (HIF1A; 603348) and Bcl2 (151430). Overexpression of Bcl2 was sufficient to induce giant osteoclasts in vivo, whereas Fra2 and Lif affected Hif1a through transcriptional modulation of the Hif prolyl hydroxylase Phd2 (606425). This pathway is operative in the placenta, because specific inactivation of Fra2 in the embryo alone did not cause hypoxia or the giant osteoclast phenotype. Bozec et al. (2008) concluded that placenta-induced hypoxia during embryogenesis leads to the formation of giant osteoclasts in young pups.
Molven et al. (1996) assigned the FRA2 gene to chromosome 2p23-p22 by fluorescence in situ hybridization.
Using GeneMatcher and other national and international networks, Cospain et al. (2022) identified 11 patients with heterozygous truncating mutations in the FOSL2 gene (see, e.g., 601575.0001-601575.0005), all within the fourth and last exon. Aplasia cutis congenita and dental enamel anomalies (ACED syndrome; 620789) were present in 9 of the patients, including 2 sisters; limited clinical information was available for 1 patient with aplasia cutis congenita, and 1 patient was reported to have only mild developmental and intellectual delay and autism spectrum disorder, features that were also present in some of the patients with scalp and dental defects. Functional analysis indicated that the FOSL2 mutants could interact with C-JUN (see 165160) and form the AP1 complex, and that the mutant proteins are subject to proteasome-mediated degradation.
Chen et al. (2024) noted that Fosl2-knockout mice die within a week after birth. Chen et al. (2024) found that mice with hematopoietic-specific deletion of Fosl2 were produced with a lower than predicted probability at weaning, suggesting possible perinatal mortality. Surviving mutant mice showed mildly reduced body size, weight loss, shortened and slightly paler bones, and mild splenomegaly compared with wildtype. Loss of Fosl2 in the hematopoietic system caused expansion of hematopoietic stem cells (HSCs) and myeloid cell growth and affected erythroid and B-cell differentiation. Fosl2 inactivation enhanced macrophage M1 polarization and stimulated proinflammatory cytokines and myeloid growth factors, skewing HSCs toward myeloid cell differentiation, similar to hematopoietic alterations in arthritic mice. The authors found that transgenic inactivation of Fosl2 in the hematopoietic system also resulted in deletion of of Fosl2 in embryonic erythro-myeloid progenitor-derived osteoclasts, leading to osteopetrosis and anemia. The reduced bone marrow cellularity in the mutant mice was due to the reduced bone marrow space in osteopetrotic mice rather than a direct role of Fosl2 in hematopoiesis. The results demonstrated that FOSL2 is indispensable for erythro-myeloid progenitor-derived osteoclasts to maintain the medullary cavity to ensure normal hematopoiesis.
In 2 sisters (patients 2 and 3) and an unrelated female patient (patient 1) with aplasia cutis-enamel dysplasia syndrome (ACED; 620789), Cospain et al. (2022) identified heterozygosity for a c.595C-T transition (c.595C-T, NM_005253.3) in exon 4 of the FOSL2 gene, resulting in an arg199-to-ter (R199X) substitution. The unaffected parents of patient 1 did not carry the mutation, indicating a de novo occurrence; the variant, which was not found in the gnomAD database, was also not present in blood DNA from the sisters' unaffected parents, suggesting germline mosaicism in a parent. Patient 1 had a skull defect underlying the aplasia cutis of her scalp, and she also exhibited autism spectrum disorder, features that were not present in the sisters. In addition, patients 1 and 2 had developmental delays and postnatal growth retardation, and patient 2 also had refractory seizures requiring amygdalohippocampectomy for treatment. Functional analysis in transfected HEK293T cells demonstrated that the R199X mutant could interact with c-JUN (see 165160) and form the AP1 complex, and that the R199X mutant is subject to proteasome-mediated degradation.
In 2 unrelated patients, 1 female and 1 male (patients 4 and 5), with aplasia cutis-enamel dysplasia syndrome (ACED; 620789), Cospain et al. (2022) identified heterozygosity for a de novo c.619C-T transition (c.619C-T NM_005253.3) in exon 4 of the FOSL2 gene, resulting in a gln207-to-ter (Q207X) substitution. The variant was not found in their unaffected parents or in the gnomAD database. Both patients had skull defects underlying the aplasia cutis of the scalp. Functional analysis in transfected HEK293T cells demonstrated that the Q207X mutant could interact with c-JUN (see 165160) and form the AP1 complex, and that the Q207X mutant is subject to proteasome-mediated degradation.
In 2 unrelated female patients (patients 7 and 8) with aplasia cutis-enamel dysplasia syndrome (ACED; 620789), Cospain et al. (2022) identified heterozygosity for a de novo 1-bp deletion (c.605del, NM_005253.3) in exon 4 of the FOSL2 gene, causing a frameshift predicted to result in a premature termination codon (Pro202GlnfsTer18). The variant was not found in their unaffected parents or in the gnomAD database. Patient 7 had a skull defect underlying the aplasia cutis of the scalp, whereas patient 8 did not. Both patients exhibited autism spectrum disorder and psychomotor delay, but patient 7, who was 20 years old, was severely impaired and had shown regression in adulthood, resulting in limited autonomy.
In a female patient (patient 6) with aplasia cutis-enamel dysplasia syndrome (ACED; 620789), Cospain et al. (2022) identified heterozygosity for a de novo 11-bp deletion (c.579_589del, NM_005253.3) in exon 4 of the FOSL2 gene, causing a frameshift predicted to result in a premature termination codon (Ser194AlafsTer61). The variant was not found in her unaffected parents or in the gnomAD database. The proband had postnatal growth retardation, mild psychomotor delays, and autism spectrum disorder.
In a 31-year-old woman (patient 9) with aplasia cutis-enamel dysplasia syndrome (ACED; 620789), Cospain et al. (2022) identified heterozygosity for a de novo 2-bp deletion (c.662_663del, NM_005253.3) in exon 4 of the FOSL2 gene, causing a frameshift predicted to result in a premature termination codon (Val221GlufsTer37). The variant was not found in her unaffected parents or in the gnomAD database. The proband had been able to speak, read, and write during childhood, but experienced regression of autonomy and showed severely impaired intellectual development when tested in adulthood.
Bozec, A., Bakiri, L., Hoebertz, A., Eferl, R., Schilling, A. F., Komnenovic, V., Scheuch, H., Priemel, M., Stewart, C. L., Amling, M., Wagner, E. F. Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 454: 221-225, 2008. [PubMed: 18548006] [Full Text: https://doi.org/10.1038/nature07019]
Chen, J., Wen, Y., Lin, L., Cui, Y., Chen, Z., Gao, J., Zhuang, Y., Chen, Q. Fosl2 deficiency predisposes mice to osteopetrosis, leading to bone marrow failure. J. Immun. 212: 1081-1093, 2024. [PubMed: 38380993] [Full Text: https://doi.org/10.4049/jimmunol.2300592]
Cospain, A., Rivera-Barahona, A., Dumontet, E., Gener, B., Bailleul-Forestier, I., Meyts, I., Jouret, G., Isidor, B., Brewer, C., Wuyts, W., Moens, L., Delafontaine, S., and 20 others. FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects. Genet. Med. 24: 2475-2486, 2022. [PubMed: 36197437] [Full Text: https://doi.org/10.1016/j.gim.2022.09.002]
Matsui, M., Tokuhara, M., Konuma, Y., Nomura, N., Ishizaki, R. Isolation of human fos-related genes and their expression during monocyte-macrophage differentiation. Oncogene 5: 249-255, 1990. [PubMed: 2107490]
Molven, A., Houge, G., Berger, R. Chromosomal assignment of the human gene encoding the Fos-related antigen-2 (FRA2) to chromosome 2p22-p23. Genomics 38: 72-75, 1996. [PubMed: 8954781] [Full Text: https://doi.org/10.1006/geno.1996.0593]