title: A missense mutation in CASK causes FG syndrome in an Italian family.
abstract: First described in 1974, FG syndrome (FGS) is an X-linked multiple congenital anomaly/mental retardation (MCA/MR) disorder, characterized by high clinical variability and genetic heterogeneity. Five loci (FGS1-5) have so far been linked to this phenotype on the X chromosome, but only one gene, MED12, has been identified to date. Mutations in this gene account for a restricted number of FGS patients with a more distinctive phenotype, referred to as the Opitz-Kaveggia phenotype. We report here that a p.R28L (c.83G-->T) missense mutation in CASK causes FGS phenotype in an Italian family previously mapped to Xp11.4-p11.3 (FGS4). The identified missense mutation cosegregates with the phenotype in this family and is absent in 1000 control X chromosomes of the same ethnic origin. An extensive analysis of CASK protein functions as well as structural and dynamic studies performed by molecular dynamics (MD) simulation did not reveal significant alterations induced by the p.R28L substitution. However, we observed a partial skipping of the exon 2 of CASK, presumably a consequence of improper recognition of exonic splicing enhancers (ESEs) induced by the c.83G-->T transversion. CASK is a multidomain scaffold protein highly expressed in the central nervous system (CNS) with specific localization to the synapses, where it forms large signaling complexes regulating neurotransmission. We suggest that the observed phenotype is most likely a consequence of an altered CASK expression profile during embryogenesis, brain development, and differentiation.
authors.affiliation: Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Napoli 80138, Italy. giulio.piluso@unina2.it
authors.forename: Giulio
authors.initials: G
authors.lastname: Piluso
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Amico
authors.forename: Valentina
authors.initials: V
authors.lastname: Saccone
authors.forename: Ettore
authors.initials: E
authors.lastname: Bismuto
authors.forename: Ida Luisa
authors.initials: IL
authors.lastname: Rotundo
authors.forename: Marina
authors.initials: M
authors.lastname: Di Domenico
authors.forename: Stefania
authors.initials: S
authors.lastname: Aurino
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics; D041321:Chromosomes, Human, X; D005190:Family; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D056892:Mediator Complex; D008995:Monoamine Oxidase / Q000235:genetics; D020125:Mutation, Missense; D016366:Open Reading Frames; D010641:Phenotype; D010766:Phosphorylation; D014157:Transcription Factors / Q000235:genetics
chemical_list: C460107:MED12 protein, human; D056892:Mediator Complex; D014157:Transcription Factors; D008995:Monoamine Oxidase; D005982:Glutathione Transferase; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1