Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy
| Autor: | Adam T. Higgins, Mitchell Goldfarb, Denise Williams, Xiaodong Wang, Anna V. Derrick, Kay Metcalfe, Ying Yang, Ronit Mesterman, Yuehua Zhang, Seo-Kyung Chung, Mark A. Tarnopolsky, Martin A. McClatchey, Sally J. Davies, Mark I. Rees, Shivaram Avula, Rajiv Mohanraj, Andrew E. Fry, William O. Pickrell, Lauren Brady, Christopher Marra, Hui Jeen Tan, Johann te Water Naude |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Gene isoform Male Heterozygote Adolescent FHF2 Mutant Mutation Missense infantile onset Biology Fibroblast growth factor X linked 03 medical and health sciences Epilepsy Exon 0302 clinical medicine Genes X-Linked Seizures Report voltage-gated sodium channel Genetics medicine Missense mutation Humans Protein Isoforms Amino Acid Sequence developmental and epileptic encephalopathy Child Gene Genetics (clinical) Neurons Brain Diseases Sodium channel Exons medicine.disease Cell biology Fibroblast Growth Factors 030104 developmental biology epileptic encephalopathy NAV1.6 Voltage-Gated Sodium Channel Gain of Function Mutation FGF13 epilepsy Female 030217 neurology & neurosurgery |
| Zdroj: | Fry, A E, Marra, C, Derrick, A V, Pickrell, W O, Higgins, A T, te Water Naude, J, McClatchey, M A, Davies, S J, Metcalfe, K A, Tan, H J, Mohanraj, R, Avula, S, Williams, D, Brady, L I, Mesterman, R, Tarnopolsky, M A, Zhang, Y, Yang, Y, Wang, X, Rees, M I, Goldfarb, M & Chung, S K 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, vol. 108, no. 1, pp. 176-185 . https://doi.org/10.1016/j.ajhg.2020.10.017 Am J Hum Genet |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2020.10.017 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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