title: Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.
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.
authors.affiliation: 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.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
authors.forename: Guy M
authors.initials: GM
authors.lastname: Lenk
authors.forename: Béatrice
authors.initials: B
authors.lastname: Dufresnois
authors.forename: Bouchra
authors.initials: B
authors.lastname: Ouled Amar Bencheikh
authors.forename: Philippe
authors.initials: P
authors.lastname: Couarch
authors.forename: Julie
authors.initials: J
authors.lastname: Renard
authors.forename: Peter A
authors.initials: PA
authors.lastname: Larson
authors.forename: Cole J
authors.initials: CJ
authors.lastname: Ferguson
authors.forename: Eric
authors.initials: E
authors.lastname: Noé
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.forename: Christine
authors.initials: C
authors.lastname: Hubans
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ferreira
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Reda
authors.initials: R
authors.lastname: Ouazzani
authors.forename: Khalid Hamid
authors.initials: KH
authors.lastname: El Hachimi
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002896:Chromosomes, Human, Pair 6; D003241:Consanguinity; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005420:Flavoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009018:Morocco; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D000072180:Phosphoinositide Phosphatases; D010744:Phosphoric Monoester Hydrolases
chemical_list: D005420:Flavoproteins; C522215:FIG4 protein, human; D010744:Phosphoric Monoester Hydrolases; C522216:Fig4 protein, mouse; D000072180:Phosphoinositide Phosphatases