Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Andrew E. Fry, Christopher Marra, Anna V. Derrick, William O. Pickrell, Adam T. Higgins, Johann te Water Naude, Martin A. McClatchey, Sally J. Davies, Kay A. Metcalfe, Hui Jeen Tan, Rajiv Mohanraj, Shivaram Avula, Denise Williams, Lauren I. Brady, Ronit Mesterman, Mark A. Tarnopolsky, Yuehua Zhang, Ying Yang, Xiaodong Wang, Mark I. ReesMitchell Goldfarb, Seo Kyung Chung

Research output: Contribution to journalArticlepeer-review

Abstract

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) 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 Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (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 Nav channel function.
Original languageEnglish
Pages (from-to)176-185
Number of pages10
JournalAmerican Journal of Human Genetics
Volume108
Issue number1
Early online date26 Nov 2020
DOIs
Publication statusPublished - 7 Jan 2021

Keywords

  • FGF13
  • FHF2
  • X linked
  • developmental and epileptic encephalopathy
  • epilepsy
  • epileptic encephalopathy
  • infantile onset
  • voltage-gated sodium channel

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