Alternative titles; symbols
HGNC Approved Gene Symbol: FGF12
Cytogenetic location: 3q28-q29 Genomic coordinates (GRCh38): 3:192,139,390-192,727,541 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q28-q29 | Developmental and epileptic encephalopathy 47 | 617166 | Autosomal dominant | 3 |
The FGF12 gene encodes a member of the fibroblast growth factor homologous factor (FHF) family, which are small cytosolic proteins that interact with the cytoplasmic tails of voltage-gated sodium channels and elevate the voltage dependence of neuronal sodium channel fast inactivation (summary by Siekierska et al., 2016).
Smallwood et al. (1996) identified and characterized 4 novel members of the fibroblast growth factor (FGF) family, including FGF12, which they referred to as fibroblast growth factor homologous factors (FHFs). The genes were identified by a combination of random cDNA sequencing, database searches, and degenerate PCR. Pairwise comparisons between the 4 FHFs show between 58% and 71% amino acid sequence identity, but each FHF shows less than 30% identity when compared with other FGFs. Like FGF1 (131220) and FGF2 (134920), the FHFs lack a classic signal sequence and contain clusters of basic residues that can act as nuclear localization signals. In transiently transfected 293 cells, FHF1 accumulates in the nucleus and is not secreted.
Fibroblast growth factors comprise a family of related polypeptides with broad mitogenic and cell survival activities. Smallwood et al. (1996) noted that FGF1, or acidic FGF, and FGF2, or basic FGF, were the first 2 family members to be identified, purified, and sequenced, and are widely expressed as a potent mitogen for a variety of cell types. FGF3 (164950) is a common target for activation by the mouse mammary tumor virus. The genes encoding FGF4 (164980), FGF5 (165190), and FGF6 (134921) have transforming activity when introduced into NIH 3T3 cells. FGF7 (148180), FGF8 (600483), and FGF9 (600921) are mitogens for keratinocytes, mammary carcinoma cells, and astrocytes, respectively. Several FGFs have been found to have additional bioactivities that were not evident during their initial identification. The FGFs are between 150 and 268 amino acid residues in length and share a conserved central region of approximately 140 amino acids. FGF signaling is generally assumed to occur by activation of transmembrane tyrosine kinase receptors. Four FGF receptors, FGFR1 (136350) through FGFR4 (134935), had been identified, and activating or inactivating receptor mutations have been described for a subset of these genes in both mice and humans.
By Southern blot hybridization of genomic DNA from rodent/human hybrid cell lines containing individual human chromosomes, Smallwood et al. (1996) demonstrated that the human FHF1 (also symbolized FGF12), FHF2 (300070), FHF3 (601514), and FHF4 (601515) genes are located on chromosomes 3, X, 17, and 13, respectively. They found that a sequence tagged site (STS) that encompassed 1 exon of FHF3 was derived from human chromosome 17 and mapped near the BRCA1 gene (113705), which is located at 17q21. The chromosomal locations of Fhf1, Fhf2, and Fhf4 in the mouse were determined using an interspecific mapping panel. Fhf1 mapped to the proximal region of mouse chromosome 16, 1.6 cM distal to somatostatin (182450) and 5.1 cM proximal to ApoD (107740). Fhf2 mapped to the mouse X chromosome and did not recombine with the CD40 ligand gene (300386) in 168 mice typed, suggesting that the 2 loci are within 1.8 cM of each other. Fhf4 mapped to the distal region of chromosome 14 and did not recombine with Rap2a (179540) in 142 mice typed in common. The Fhf3 gene was not mapped with the backcross panel because it failed to demonstrate an informative RFLP when tested with 14 restriction enzymes. The proximity of the human FHF3 gene to BRCA1 suggested to Smallwood et al. (1996) that the mouse homolog resides on chromosome 11 in the region that is syntenic with the BRCA1 region of human chromosome 17. From the location of the Fhf1 gene in the mouse one can infer that the human gene is located on 3q28. Smallwood et al. (1996) showed that FHFs are expressed principally in the nervous system and are therefore likely to play a role in nervous system development and/or function.
Liu and Chiu (1997) mapped the FGF12 gene to 3q29-qter by fluorescence in situ hybridization.
In 2 sibs with developmental and epileptic encephalopathy-47 (DEE47; 617166), Siekierska et al. (2016) identified a de novo heterozygous missense mutation in the FGF12 gene (R114H; R52H in the B isoform; 601513.0001). The mutation, which was found by exome sequencing, was not present in either parent, suggesting germline mosaicism. In vitro functional expression studies in neuronal cells and in zebrafish showed that the mutation resulted in a gain-of-function effect with increased neuronal excitability and epileptiform activity in zebrafish.
Al-Mehmadi et al. (2016) identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with DEE47. The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of Siekierska et al. (2016), suggested that DEE47 is an FGF12 R52H mutation-specific disease.
Guella et al. (2016) identified a de novo heterozygous R52H mutation in 2 unrelated patients with DEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. Guella et al. (2016) noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age. The findings significantly expanded the phenotype associated with this specific mutation, suggesting that other genetic and/or environmental factors may be involved.
By whole-exome sequencing in 2 unrelated Japanese patients with DEE47, Takeguchi et al. (2018) identified heterozygosity for the R114H mutation in the FGF12 gene. Both patients started having seizures a few days after birth; patient 1 was diagnosed with early infantile epileptic encephalopathy, and patient 2 was diagnosed with epilepsy of infancy with migrating focal seizures, which responded well to phenytoin and high-dose phenobarbital. The phenotypically normal mother of patient 1 was found to be mosaic for the mutation. The authors noted that DEE47 is associated with diverse phenotypes and may respond to sodium channel blocker or high-dose phenobarbital.
In 2 sibs with developmental and epileptic encephalopathy-47 (DEE47; 617166), Siekierska et al. (2016) identified a de novo heterozygous C-to-T transition (chr3.192,053,223C-T, GRCh37) in the FGF12 gene, resulting in an arg114-to-his (R114H) substitution in the A-isoform and an arg52-to-his (R52H) substitution in the B-isoform. The mutation, which was found by exome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. It was also not present in either parent, suggesting germline mosaicism. The substitution occurs at a highly conserved residue that binds the cytoplasmic tail of voltage-gated sodium channels necessary for modulation of fast inactivation. In vitro functional expression studies in neuronal cells showed that both the R114H and R52H variants strongly changed the voltage dependence of inactivation gating, resulting in a gain-of-function effect and increased neuronal excitability. Additional experiments with different substitutions of the arg114 residue indicated that the loss of arginine side-chain interactions with the channel likely causes impaired function. Transfection of the orthologous mutation in zebrafish caused epileptiform activity in larval optic tecta.
Al-Mehmadi et al. (2016) identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with DEE47. Whole-exome or whole-genome sequencing in these patients detected a c.155G-A transition (c.155G-A, NM_004113.5); the mutation was confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of Siekierska et al. (2016), suggested that DEE47 is an FGF12 R52H mutation-specific disease. The patients had onset of seizures in the first days to weeks of life.
Guella et al. (2016) identified a de novo heterozygous c.155G-A transition in the FGF12 gene, resulting in an R52H substitution, in 2 unrelated patients with DEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. Guella et al. (2016) noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age.
By whole-exome sequencing in 2 unrelated Japanese patients with DEE47 (617166), Takeguchi et al. (2018) identified a heterozygous c.341G-A transition (c.341G-A, NM_021032.4) in the FGF12 gene, resulting in an R114H substitution. In patient 1, the mutation was inherited from a phenotypically normal mother who was mosaic for the mutation; in patient 2, the mutation occurred de novo.
Al-Mehmadi, S., Splitt, M., Ramesh, V., DeBrosse, S., Dessoffy, K., Xia, F., Yang, Y., Rosenfeld, J. A., Cossette, P., Michaud, J. L., Hamdan, F. F., Campeau, P. M., Minassian, B. A. FHF1 (FGF12) epileptic encephalopathy. Neurol. Genet. 2: e115, 2016. Note: Electronic Article. [PubMed: 27830185] [Full Text: https://doi.org/10.1212/NXG.0000000000000115]
Guella, I., Huh, L., McKenzie, M. B., Toyota, E. B., Bebin, E. M., Thompson, M. L., Cooper, G. M., Evans, D. M., Buerki, S. E., Adam, S., Van Allen, M. I., Nelson, T. N., Connolly, M. B., Farrer, M. J., Demos, M. De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy. Neurol. Genet. 2: e120, 2016. Note: Electronic Article. [PubMed: 27872899] [Full Text: https://doi.org/10.1212/NXG.0000000000000120]
Liu, Y., Chiu, I.-M. Assignment of FGF12, the human FGF homologous factor 1 gene, to chromosome 3q29-3qter by fluorescence in situ hybridization. Cytogenet. Cell Genet. 78: 48-49, 1997. [PubMed: 9345906] [Full Text: https://doi.org/10.1159/000134625]
Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P. A. M., Van Esch, H., Goldfarb, M., Buyse, G. M. Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology 86: 2162-2170, 2016. [PubMed: 27164707] [Full Text: https://doi.org/10.1212/WNL.0000000000002752]
Smallwood, P. M., Munoz-Sanjuan, I., Tong, P., Macke, J. P., Hendry, S. H. C., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development. Proc. Nat. Acad. Sci. 93: 9850-9857, 1996. [PubMed: 8790420] [Full Text: https://doi.org/10.1073/pnas.93.18.9850]
Takeguchi, R., Haginoya, K., Uchiyama, Y., Fujita, A., Nagura, M., takeshita, E., Inui, T., Okubo, Y., Sato, R., Miyabayashi, T., Togashi, N., Saito, T., Nakagawa, E., Sugai, K., Nakashima, M., Saitsu, H., Matsumoto, N., Sasaki, M. Two Japanese cases of epileptic encephalopathy associated with an FGF12 mutation. Brain Dev. 40: 728-732, 2018. [PubMed: 29699863] [Full Text: https://doi.org/10.1016/j.braindev.2018.04.002]