2. Academic Validation
  3. Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy

Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy

  • Neurology. 2016 Jun 7;86(23):2162-70. doi: 10.1212/WNL.0000000000002752.
Aleksandra Siekierska 1,  Mala Isrie 1,  Yue Liu 1,  Chloë Scheldeman 1,  Niels Vanthillo 1,  Lieven Lagae 1,  Peter A M de Witte 1,  Hilde Van Esch 1,  Mitchell Goldfarb 1,  Gunnar M Buyse 2
Affiliations

Affiliations

  • 1 From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
  • 2 From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY. [email protected].
PMID: 27164707 DOI: 10.1212/WNL.0000000000002752
Abstract

Objective: Voltage-gated Sodium Channel (Nav)-encoding genes are among early-onset epileptic encephalopathies (EOEE) targets, suggesting that other genes encoding Nav-binding proteins, such as Fibroblast Growth Factor homologous factors (FHFs), may also play roles in these disorders.

Methods: To identify additional genes for EOEE, we performed whole-exome sequencing in a family quintet with 2 siblings with a lethal disease characterized by EOEE and cerebellar atrophy. The pathogenic nature and functional consequences of the identified sequence alteration were determined by electrophysiologic studies in vitro and in vivo.

Results: A de novo heterozygous missense mutation was identified in the FHF1 gene (FHF1AR114H, FHF1BR52H) in the 2 affected siblings. The mutant FHF1 proteins had a strong gain-of-function phenotype in transfected Neuro2A cells, enhancing the depolarizing shifts in Nav1.6 voltage-dependent fast inactivation, predicting increased neuronal excitability. Surprisingly, the gain-of-function effect is predicted to result from weaker interaction of mutant FHF1 with the Nav cytoplasmic tail. Transgenic overexpression of mutant FHF1B in zebrafish larvae enhanced epileptiform discharges, demonstrating the epileptic potential of this FHF1 mutation in the affected children.

Conclusions: Our data demonstrate that gain-of-function FHF mutations can cause neurologic disorder, and expand the repertoire of genetic causes (FHF1) and mechanisms (altered Nav gating) underlying EOEE and cerebellar atrophy.

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