Fever is a highly conserved systemic response to infection dating back over 600 million years. Although conferring a survival benefit, fever can negatively impact the function of excitable tissues, such as the heart, producing cardiac arrhythmias. Here we show that mice lacking fibroblast growth factor homologous factor 2 (FHF2) have normal cardiac rhythm at baseline, but increasing core body temperature by as little as 3 °C causes coved-type ST elevations and progressive conduction failure that is fully reversible upon return to normothermia. FHF2-deficient cardiomyocytes generate action potentials upon current injection at 25 °C but are unexcitable at 40 °C. The absence of FHF2 accelerates the rate of closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation rate to severely suppress cardiac sodium currents at elevated temperatures. Our experimental and computational results identify an essential role for FHF2 in dictating myocardial excitability and conduction that safeguards against temperature-sensitive conduction failure.

Neurons in vertebrate central nervous systems initiate and conduct sodium action potentials in distinct subcellular compartments that differ architecturally and electrically. Here, we report several unanticipated passive and active properties of the cerebellar granule cell's unmyelinated axon. Whereas spike initiation at the axon initial segment relies on sodium channel (Na v )-associated fibroblast growth factor homologous factor (FHF) proteins to delay Na v inactivation, distal axonal Na v s show little FHF association or FHF requirement for high-frequency transmission, velocity and waveforms of conducting action potentials. In addition, leak conductance density along the distal axon is estimated as o1% that of somatodendritic membrane. The faster inactivation rate of FHF-free Na v s together with very low axonal leak conductance serves to minimize ionic fluxes and energetic demand during repetitive spike conduction and at rest. The absence of FHFs from Na v s at nodes of Ranvier in the central nervous system suggests a similar mechanism of current flux minimization along myelinated axons.

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na v ) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi-and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Na v channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na v 1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Na v channel function.Voltage-activated sodium channels (Na v ) play an essential role in the generation and spread of action potentials in excitable tissues. 1,2 Variants in Na v channels and their regulatory partners are a major cause of infantile-onset developmental and epileptic encephalopathies (DEEs). 3,4 DEEs are typically associated with developmental delay or regression, treatment-resistant seizures, and electroencephalographic abnormalities. 5,6 The developmental consequences of DEEs are due to frequent epileptiform activity in combination with the direct effects of the genetic variant. 7,8 Fibroblast growth factor homologous factors (FHFs) are intracellular proteins that bind to the C-terminal domain of Na v channels to modulate their function and location. [9][10][11][12] FHFs were initially identified due to their homology with fibroblast growth factors (FGFs). 13 However, FHFs are not secreted by cells and have only limited ability to activate FGF receptors. 9,14,15 There are four FHF genes in mammals (often referred to by their FGF names): FHF1 (FGF12 [MIM: 601513]), FHF2 (FGF13 [MIM: 300070]), FHF3 (FGF11 [MIM: 601514]), and FHF4 (FGF14 [MIM: 601515]). 9 The FHF genes have multiple transcription initiation sites. The alternative first exons produces multiple isoforms with variable N-terminal domains. 16 The isoforms differ in their localization and ability to regulate Na v channels. 9 FHF2, located at Xq26.3-q27.1, is highly expressed in the developing and adult brain. 9,13 FHF2 is also expressed in endocrine tissues, ovaries, skeletal muscle, and the myocardium of the developing heart. [17][18][19] FHF2 has been implicated...

Objective: Fibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel-binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain-of-function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice. Methods: The Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate Fhf1 R52H/F+ mice. Spontaneous epileptiform events in Fhf1 R52H/+ mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure-induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1B R52H protein was assayed by voltageclamp recordings of FHF-deficient mouse cardiomyocytes infected with adenoviruses expressing wild-type FHF1B or FHF1B R52H protein. Results: All Fhf1 R52H/+ mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26 days of age. EEG recordings in 19-20-day-old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures