2. Academic Validation
  3. Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria

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

  • Neurology. 2014 Mar 25;82(12):1068-75. doi: 10.1212/WNL.0000000000000241.
Stéphanie Baulac 1,  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
Affiliations

Affiliation

  • 1 From INSERM (S.B., B.D., B.O.A.B., P.C., J.R., E.N., K.H.E.H., E.L.), U1127; Sorbonne Universités, UPMC Univ Paris 06 (S.B., B.D., B.O.A.B., P.C., J.R., E.N., K.H.E.H., E.L.), UM 75; CNRS (S.B., B.D., B.O.A.B., P.C., J.R., E.N., K.H.E.H., E.L.), UMR 7225, ICM, Paris, ICM, (S.B., B.D., B.O.A.B., P.C., J.R., E.N., K.H.E.H., E.L.) Paris, F-75013 Paris, France; Department of Human Genetics (G.M.L., P.A.L., C.J.F., M.H.M.), University of Michigan, Ann Arbor; Service de Neurophysiologie Clinique (B.O.A.B.), Hôpital des Spécialités, Centre Hospitalier Ibn Sina Rabat, Morocco; Genetics and Pathophysiology of Neurodevelopmental and Neuromuscular Diseases (K.P.), Cochin Institute, Paris; GenoScreen (C.H., S.F.), Lille, France; Neuroscience Department (R.G.), Children's Hospital A. Meyer, University of Florence and IRCCS Stella Maris, Pisa, Italy; Laboratoire de Neurogénétique (K.H.E.H.), Ecole Pratique des Hautes Etudes, Paris; and Département de Génétique et de Cytogénétique (E.L.), AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France.
PMID: 24598713 DOI: 10.1212/WNL.0000000000000241
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.

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