Alternative titles; symbols
HGNC Approved Gene Symbol: FGF14
SNOMEDCT: 719252002;
Cytogenetic location: 13q33.1 Genomic coordinates (GRCh38) : 13:101,710,804-102,402,443 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q33.1 | Spinocerebellar ataxia 27A | 193003 | Autosomal dominant | 3 |
| Spinocerebellar ataxia 27B, late-onset | 620174 | Autosomal dominant | 3 |
The FGF14 gene encodes fibroblast growth factor-14, which is highly expressed in the brain, particularly in Purkinje cells where it interacts with voltage-gated channels to regulate neuronal excitability. FGF14 also plays a role in synaptic plasticity and neurogenesis in the hippocampus (summary by Piarroux et al., 2020).
FGF14 belongs to a subclass of fibroblast growth factors that are expressed in the developing and adult central nervous system (Smallwood et al., 1996). For a discussion on the FHF gene family, see FGF12 (FHF1; 601513).
Smallwood et al. (1996) identified and characterized 4 novel members of the fibroblast growth factor (FGF) family, including FGF14, which they called FHF4. The genes were identified by a combination of random cDNA sequencing, database searches, and degenerate PCR.
Wang et al. (2000) characterized 2 mouse isoforms of Fgf14, which they called Fgf14-1a and Fgf14-1b, resulting from alternative first exons. In situ hybridization showed that Fgf14 is widely expressed in mouse brain, spinal cord, major arteries, and thymus between embryonic days 12.5 and 14.5. In mouse cerebellar development, Fgf14 was first observed at postnatal day 1 in postmitotic granule cells and later in migrating and postmigratory granule cells. The Fgf14 expression pattern in cerebellum was complementary to that of Math1 (ATOH1; 601461), a marker for proliferating granule cells in the external germinal layer.
By Southern blot hybridization of genomic DNA from rodent/human hybrid cell lines carrying individual human chromosomes, Smallwood et al. (1996) mapped the FGF14 gene to chromosome 13. Using an interspecific backcross mapping panel, they mapped the mouse homolog to chromosome 14, very close to the Rap2a (179540) gene, which in the human maps to 13q34.
Miura et al. (2019) stated that the FGF14 gene maps to chromosome 13q33.1.
Spinocerebellar Ataxia 27A
In a large 3-generation Dutch family with spinocerebellar ataxia-27A (SCA27A; 193003), van Swieten et al. (2003) identified a heterozygous missense mutation in the FGF14 gene (F145S; 601515.0001). The disorder was consistent with the occurrence of ataxia and paroxysmal dyskinesia in Fgf14 knockout mice (Wang et al., 2002).
In 1 of 208 unrelated patients with familial ataxia, Dalski et al. (2005) identified a heterozygous 1-bp deletion in the FGF14 gene (601515.0002). The patient had early onset of the disorder and mildly impaired intellectual development.
By whole-exome sequencing of genes known to cause SCA in a 62-year-old affected Japanese man, Miura et al. (2019) identified a heterozygous nonsense mutation in the FGF14 gene (K177X; 601515.0003). The patient's father was reportedly affected, but neither detailed clinical information nor DNA was available for him. The variant was not found in public databases or in 502 Japanese controls.
In a mother and her 3 sons, of French Canadian origin, with variable manifestations of SCA27A, Choquet et al. (2015) identified a heterozygous frameshift mutation in the FGF14 gene (601515.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not reported, but the authors postulated haploinsufficiency and suggested that SCA27 may be a type of channelopathy characterized by impaired function of voltage-gated ion channels due to mutation in the FGF14 gene.
In 7 affected members of a large multigenerational family (family A) with variable manifestations of SCA27A, Piarroux et al. (2020) identified a heterozygous nonsense mutation in the FGF14 gene (E147X; 601515.0005). An unrelated girl with SCA27A was found to carry a different mutation in the FGF14 gene (Y162X). The mutations, which were found by direct Sanger sequencing of a limited gene panel, segregated with the disorder in family A. Functional studies of the variants and studies of patient cells were not performed.
Late-Onset Spinocerebellar Ataxia 27B
In 128 patients, mostly of European or French Canadian descent, with late-onset spinocerebellar ataxia-27B (SCA27B; 620174), Pellerin et al. (2023) identified a heterozygous trinucleotide (GAA)n repeat expansion (equal to or greater than 250 repeats) in intron 1 of the FGF14 gene, which is included in pre-mRNA transcript 2 and not in pre-mRNA transcript 1 (601515.0006). The GAA repeat was initially found in 21 affected individuals from 3 large multigenerational French Canadian families who underwent genome sequencing specifically looking for pathogenic repeat expansions. Subsequently, 4 independent cohorts of patients from different populations with unsolved late-onset cerebellar ataxia were screened for this FGF14 repeat expansion. GAA expansions equal to or greater than 250 repeats were found in 40 (61%) of 66 French Canadian patients, compared to 1% of controls; in 42 (18%) of 228 German patients, compared to 3% of controls; in 3 (15%) of 20 Australian patients, and in 3 (10%) of 31 East Asian Indian patients. The data suggested that 250 to 300 GAA expansions are likely to be pathogenic, although with incomplete penetrance, and that expansions greater than 300 are fully penetrant. Studies of patient cerebellar tissue and patient induced pluripotent stem cells (iPSCs) differentiated into motor neurons showed decreased FGF14 expression, suggesting haploinsufficiency as the pathogenetic mechanism.
Rafehi et al. (2023) identified a GAA(n) repeat expansion in intron 1 of the FGF14 gene in patients with autosomal dominant adult-onset ataxia. Their results strongly supported a fully penetrant threshold of GAA(335) or greater and suggested that repeats between GAA(250) and GAA(335) is likely pathogenic, although with incomplete penetrance.
To study the role of Fgf14 in CNS development and adult brain function, Wang et al. (2002) generated Fgf14-deficient mice that expressed an FGF14/beta-galactosidase fusion protein in place of the normal Fgf14 protein. The Fgf14-deficient mice were viable, fertile, and anatomically normal, but developed ataxia and a paroxysmal hyperkinetic movement disorder. The authors noted that the motor abnormalities are associated with dysfunction of the basal ganglia system and resemble several human dystonia syndromes. Using neuropharmacologic studies, Wang et al. (2002) showed that the Fgf14-deficient mice had reduced responses to dopamine agonists. They suggested a function for Fgf14 in neuronal signaling, axonal trafficking, and synaptosomal function.
In affected members of a 3-generation Dutch family with autosomal dominant spinocerebellar ataxia-27A (SCA27A; 193003), van Swieten et al. (2003) identified a heterozygous phe145-to-ser (F145S) mutation in the FGF14 gene. As indicated by protein modeling, the amino acid change was predicted to reduce the stability of the protein.
Laezza et al. (2007) found that expression of human FGF14 with the F145S mutation in cultured rat hippocampal neurons markedly reduced localization of voltage-gated sodium channel alpha subunits to the axonal initial segment (AIS) compared with controls. Mutant FGF14 acted as a dominant negative and suppressed peak sodium channel current densities and excitability of hippocampal neurons. The authors proposed that FGF14 likely forms oligomers and that interaction between wildtype and mutant FGF14 in heterozygotes disrupts normal association between FGF14 and voltage-gated sodium channel alpha subunits at the AIS.
In a patient with spinocerebellar ataxia-27A (SCA27A; 193003), Dalski et al. (2005) identified a heterozygous 1-bp deletion (487delA) in exon 4 of the FGF14 gene, resulting in premature termination of the protein and loss of one-third of amino acid residues. The mutation was not identified in 208 control samples. The patient had early onset of the disorder and mild mental retardation.
By whole-exome sequencing of genes known to cause spinocerebellar ataxia in a 62-year-old Japanese man with SCA (SCA27A; 193003), Miura et al. (2019) identified a heterozygous c.529A-T transversion (c.529A-T, NM_004115) in exon 4 of the FGF14 gene, predicting a lys177-to-ter (K177X) substitution with loss of the heparin-binding sites in the FGF domain. The authors suggested haploinsufficiency as the pathogenic mechanism. The variant was not found in public databases or in 502 Japanese controls. The patient's father was reportedly affected, but there was no detailed clinical information or DNA available for him.
In a mother and her 3 sons, of French Canadian origin, with variable manifestations of spinocerebellar ataxia-27A (SCA27A; 193003), Choquet et al. (2015) identified a heterozygous 1-bp insertion, c.211_212insA (chr3:102,527,628_102,527,629insT, hg19), in exon 2 of the FGF14 gene, resulting in a frameshift and premature termination (Ile71AsnfsTer27). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in 600 French Canadian controls. Functional studies of the variant and studies of patient cells were not reported, but the authors postulated haploinsufficiency and suggested that SCA27 may be a type of channelopathy characterized by impaired function of voltage-gated ion channels due to mutation in the FGF14 gene. The proband developed features of episodic ataxia in his late twenties that later progressed to permanent cerebellar ataxia with dysarthria and tremor. All 4 individuals had sustained nystagmus.
In 7 affected members of a large multigenerational family (family A) with variable manifestations of spinocerebellar ataxia-27A (SCA27A; 193003), Piarroux et al. (2020) identified a heterozygous c.439G-T transversion (c.439G-T, NM_004115.3) in the FGF14 gene, resulting in a glu147-to-ter (E147X) substitution. The mutation, which was found by direct Sanger sequencing of a limited gene panel, segregated with the disorder in the family. Other family members were reported as having hand tremor since childhood, but genetic testing was not performed. Functional studies of the variant and studies of patient cells were not performed. There was intrafamilial variability in age at onset and clinical manifestations: some had paroxysmal episodes consistent with episodic ataxia, whereas others had only postural tremor or nystagmus.
In 128 patients, mostly of European of French Canadian descent, with late-onset spinocerebellar ataxia-27B (SCA27B; 620174), Pellerin et al. (2023) identified a heterozygous trinucleotide (GAA)n repeat expansion (equal to or greater than 250 repeats) in intron 1 of the FGF14 gene, which is included in pre-mRNA transcript 2 (NM_175929.3) and not in pre-mRNA transcript 1. The GAA repeat was initially found in 21 affected individuals from 3 large multigenerational French Canadian families who underwent genome sequencing specifically looking for pathogenic repeat expansions. The number of repeat units was greater than 300 in all but 1, who had 250 repeat units. One of the patients carried expansions on both alleles (300/716). The expansions, which were confirmed by Sanger sequencing, segregated with the disorder in the families in a pattern consistent with autosomal dominant inheritance. Eight (0.98%) of 816 control chromosomes carried an expansion of at least 250 triplet repeats, and none had a GAA expansion over 300 repeats. Subsequently, 4 independent cohorts of patients from different populations with unsolved late-onset cerebellar ataxia were screened for this FGF14 repeat expansion. GAA expansions equal to or greater than 250 repeats were found in 40 (61%) of 66 French Canadian patients, compared to 1% of controls; in 42 (18%) of 228 German patients, compared to 3% of controls; in 3 (15%) of 20 Australian patients, and in 3 (10%) of 31 East Asian Indian patients. The expansion was also present in affected relatives of some of the families. The repeat expansions were detected by long-range PCR, gel electrophoresis, and targeted long-range nanopore sequencing. Haplotype analysis of 5 French Canadian families was consistent with a founder effect in this population, but the authors noted that there were 2 Turkish and 3 Indian patients, suggesting that this repeat expansion may arise on multiple haplotype backgrounds. The findings also demonstrated that there is a high degree of polymorphism of this repeat locus in the general population. The data suggested that 250 to 300 GAA expansions are likely to be pathogenic, although with incomplete penetrance, and that expansions greater than 300 are fully penetrant. A study of 30 meiotic events showed that the transmission of expanded GAA alleles resulted in expansion in the female germline and contraction in the male germline. This was associated with an observed reduced paternal inheritance (30%). Postmortem cerebellar tissue derived from 2 patients and motor neurons derived from induced pluripotent stem cells (iPSCs) from 2 other patients showed decreased expression of total FGF14 and FGF14 transcript 2 and decreased levels of the protein, suggesting that the intronic GAA expansion interferes with FGF14 transcription. The findings were consistent with haploinsufficiency as the pathogenetic mechanism. The mean age at onset of episodic symptoms and progressive ataxia, respectively, was 55 and 59 years; none of the patients were under the age of 30. The authors postulated that this disorder may be a type of channelopathy.
Rafehi et al. (2023) identified a GAA(n) repeat expansion in intron 1 of the FGF14 gene in patients with autosomal dominant adult-onset ataxia. Among a cohort of 95 affected Australian individuals, 13 carried an allele greater than GAA(250), 4 of whom had more than 335 GAA repeats. Only 2 controls (0.6%) had a pure GAA expanded allele greater than GAA(250), with the maximum size being GAA(300). These data suggested that heterozygous expansion of a pure GAA repeat in FGF14 (over 250 repeats) represents a common cause of ataxia (OR = 24.3). A replication cohort of 104 German individuals with ataxia identified 9 (8.7%) patients with more than 335 GAA repeats and 6 (5.8%) with between 250 and 335 repeats, whereas 10 (5.3%) controls had more than 250 GAA repeats, but none had more than 335 GAA repeats. These data strongly supported a fully penetrant threshold of GAA(335) or greater and suggested that GAA(250) or greater is likely pathogenic, although with incomplete penetrance. The primary site of expression of the long isoform of FGF14 (1b) is in the brain. The GAA(n) repeat expansion is located within intron 1 of isoform 1b, suggesting that it may interfere with gene transcription. Functional studies of patient fibroblasts were inconclusive because FGF14 is not strongly expressed in those cells. The authors hypothesized that the pathogenic mechanism is reduced functional protein due to decreased expression of the allele with the expanded repeat.
Choquet, K., La Piana, R., Brais, B. A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia. Neurogenetics 16: 233-236, 2015. [PubMed: 25566820] [Full Text: https://doi.org/10.1007/s10048-014-0436-7]
Dalski, A., Atici, J., Kreuz, F. R., Hellenbroich, Y., Schwinger, E., Zuhlke, C. Mutation analysis in the fibroblast growth factor 14 gene: frameshift mutation and polymorphisms in patients with inherited ataxias. Europ. J. Hum. Genet. 13: 118-120, 2005. [PubMed: 15470364] [Full Text: https://doi.org/10.1038/sj.ejhg.5201286]
Laezza, F., Gerber, B. R., Lou, J. Y., Kozel, M. A., Hartman, H., Craig, A. M., Ornitz, D. M., Nerbonne, J. M. The FGF14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. J. Neurosci. 27: 12033-12044, 2007. [PubMed: 17978045] [Full Text: https://doi.org/10.1523/JNEUROSCI.2282-07.2007]
Miura, S., Kosaka, K., Fujioka, R., Uchiyama, Y., Shimojo, T., Morikawa, T., Irie, A., Taniwaki, T., Shibata, H. Spinocerebellar ataxia 27 with a novel nonsense variant (lys177X) in FGF14. Europ. J. Med. Genet. 62: 172-176, 2019. [PubMed: 30017992] [Full Text: https://doi.org/10.1016/j.ejmg.2018.07.005]
Pellerin, D., Danzi, M. C., Wilke, C., Renaud, M., Fazal, S., Dicaire, M.-J., Scriba, C. K., Ashton, C., Yanick, C., Beijer, D., Rebelo, A., Rocca, C., and 40 others. Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. New Eng. J. Med. 388: 128-141, 2023. [PubMed: 36516086] [Full Text: https://doi.org/10.1056/NEJMoa2207406]
Piarroux, J., Riant, F., Humbertclaude, V., Remerand, G., Hadjadj, J., Rejou, F., Coubes, C., Pinson, L., Meyer, P., Roubertie, A. FGF14-related episodic ataxia: delineating the phenotype of episodic ataxia type 9. Ann. Clin. Transl. Neurol. 7: 565-572, 2020. [PubMed: 32162847] [Full Text: https://doi.org/10.1002/acn3.51005]
Rafehi, H., Read, J., Szmulewicz, D. J., Davies, K. C., Snell, P., Fearnley, L. G., Scott, L., Thomsen, M., Gillies, G., Pope, K., Bennett, M. F., Munro, J. E., and 19 others. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am. J. Hum. Genet. 110: 105-119, 2023. Note: Erratum: Am. J. Hum. Genet. 110: 1018 only, 2023. [PubMed: 36493768] [Full Text: https://doi.org/10.1016/j.ajhg.2022.11.015]
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]
van Swieten, J. C., Brusse, E., de Graaf, B. M., Krieger, E., van de Graaf, R., de Koning, I., Maat-Kievit, A., Leegwater, P., Dooijes, D., Oostra, B. A., Heutink, P. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia. Am. J. Hum. Genet. 72: 191-199, 2003. Note: Erratum: Am. J. Hum. Genet. 72: 1078 only, 2003. [PubMed: 12489043] [Full Text: https://doi.org/10.1086/345488]
Wang, Q., Bardgett, M. E., Wong, M., Wozniak, D. F., Lou, J., McNeil, B. D., Chen, C., Nardi, A., Reid, D. C., Yamada, K., Ornitz, D. M. Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 35: 25-38, 2002. [PubMed: 12123606] [Full Text: https://doi.org/10.1016/s0896-6273(02)00744-4]
Wang, Q., McEwen, D. G., Ornitz, D. M. Subcellular and developmental expression of alternatively spliced forms of fibroblast growth factor 14. Mech. Dev. 90: 283-287, 2000. [PubMed: 10640713] [Full Text: https://doi.org/10.1016/s0925-4773(99)00241-5]