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

Fry, Andrew E., Marra, Christopher, Derrick, Anna V., Pickrell, William O., Higgins, Adam T., te Water Naude, Johann, McClatchey, Martin A., Davies, Sally J., Metcalfe, Kay A., Tan, Hui Jeen, Mohanraj, Rajiv, Avula, Shivaram, Williams, Denise, Brady, Lauren I., Mesterman, Ronit, Tarnopolsky, Mark A., Zhang, Yuehua, Yang, Ying, Wang, Xiaodong, Rees, Mark I., Goldfarb, Mitchell and Chung, Seo-Kyung 2021. Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy. American Journal of Human Genetics 108 (1) , pp. 176-185. 10.1016/j.ajhg.2020.10.017

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Abstract

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 v1.6 (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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier (Cell Press)
ISSN: 0002-9297
Date of First Compliant Deposit: 27 November 2020
Date of Acceptance: 30 October 2020
Last Modified: 26 Nov 2021 10:51
URI: http://orca.cardiff.ac.uk/id/eprint/136659

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