Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria

Stéphanie Baulac, Guy M. Lenk, Béatrice Dufresnois, Bouchra Ouled Amar Bencheikh, Philippe Couarch, Julie Renard, Peter A. Larson, Cole J. Ferguson, Eric Noé, Karine Poirier, Christine Hubans, Stéphanie Ferreira, Renzo Guerrini, Reda Ouazzani, Khalid Hamid El Hachimi, Miriam H. Meisler, Eric Leguern

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Objective: The aim of this study was to identify the causal gene in a consanguineous Moroccan family with temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy, previously mapped to the 6q16-q22 region. Methods: We used exome sequencing and analyzed candidate variants in the 6q16-q22 locus, as well as a rescue assay in Fig4-null mouse fibroblasts and immunohistochemistry of Fig4-null mouse brains. Results: A homozygous missense mutation (p.Asp783Val) in the phosphoinositide phosphatase gene FIG4 was identified. Pathogenicity of the variant was supported by impaired rescue of the enlarged vacuoles in transfected fibroblasts from Fig4-deficient mice. Histologic examination of Fig4-null mouse brain revealed neurodevelopmental impairment in the hippocampus, cortex, and cerebellum as well as impaired cerebellar gyration/foliation reminiscent of human cortical malformations. Conclusions: This study extends the spectrum of phenotypes associated with FIG4 mutations to include cortical malformation associated with seizures and psychiatric manifestations, in addition to the previously described Charcot-Marie-Tooth disease type 4J and Yunis-Varón syndrome.

Original languageEnglish
Pages (from-to)1068-1075
Number of pages8
JournalNeurology
Volume82
Issue number12
DOIs
StatePublished - Mar 25 2014
Externally publishedYes

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