FGF14
FGF14 (Fibroblast Growth Factor 14) is an atypical member of the fibroblast growth factor family. Unlike classical FGFs, it is not secreted and does not act as a ligand for FGF receptors. Instead, it functions intracellularly, primarily within the central nervous system.
Key Features
Gene location: Chromosome 13q33.1 (human)
Expression: Highly expressed in the brain, including the cerebellum, hippocampus, and cerebral cortex
Main function: Modulates voltage-gated sodium channels (Nav), particularly at the axon initial segment. This affects neuronal excitability, action potential initiation, and signal propagation.
Protein interactions: Binds to Nav α-subunits (e.g., Nav1.6), regulating their trafficking, localization, and kinetics.
Clinical Relevance
Mutations in FGF14 are linked to:
Spinocerebellar ataxia type 27 (SCA27):
Autosomal dominant neurodegenerative disorder
Onset often in childhood or adolescence
Characterized by ataxia, tremor, dysarthria, and sometimes cognitive impairment
Epilepsy and neuropsychiatric disorders: Due to its role in ion channel modulation, FGF14 dysfunction has also been implicated in epilepsy, bipolar disorder, and schizophrenia in some studies.
Animal Models
Fgf14 knockout mice show:
Gait ataxia
Motor hyperactivity
Impaired hippocampal-dependent learning These phenotypes resemble aspects of human SCA27 and support FGF14's critical role in neuronal function.
An intronic repeat expansion (GAA∙TTC)exp in the FGF14 gene (FGF14 (GAA∙TTC)exp) has recently been found to cause dominantly inherited ataxia SCA27B. The core phenotype consists of late-onset and slowly progressing ataxia with down-beat nystagmus and episodic features. Disease penetrance depends on the number of repeat units and ≥300 is widely used pathogenic threshold for complete penetrance. The Finnish population is genetically unique and SCA27B has not previously been reported in Finland.
Methods: We investigated FGF14 (GAA∙TTC)exp in a cohort of 96 Finnish patients with suspected hereditary ataxia or ataxia of unknown etiology, of whom 62 patients had no previous genetic diagnosis. We also assessed FGF14 (GAA∙TTC)exp in 561 controls in order to estimate its population prevalence in North Ostrobothnia.
Results: We found five patients with FGF14 (GAA∙TTC)≥250 giving a frequency of 5.2 % in the ataxia cohort. One patient had a rare biallelic genotype. Four patients had the classical SCA27B phenotype with no atypical features. Two of the patients had a previous genetic diagnosis and digenic contribution could not be excluded. Moreover, we found one patient with suspected FGF14 disease and with (GAA∙TTC)248, but the segregation analysis remained inconclusive. The (GAA∙TTC)≥250 frequency was 2.7 % in the general population. Population prevalence was 1.7 per 100 000 in North Ostrobothnia. The frequency of alleles harboring 200-249 repeats was 2.2 % in patients and 1.5 % in controls.
Conclusion: Our results suggest that screening of FGF14 expansion should be carried out in Finnish patients with suspected hereditary ataxia or ataxia of unknown etiology 1).