A missense mutation in CASK causes FG syndrome in an Italian family

Giulio Piluso, Francesca D'Amico, Valentina Saccone, Ettore Bismuto, Ida Luisa Rotundo, Marina Di Domenico, Stefania Aurino, Charles E. Schwartz, Giovanni Neri, Vincenzo Nigro

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)162-177
Number of pages16
JournalAmerican Journal of Human Genetics
Volume84
Issue number2
DOIs
Publication statusPublished - Aug 8 2008

Fingerprint

Missense Mutation
Phenotype
X Chromosome
Genetic Heterogeneity
Molecular Dynamics Simulation
Mental Disorders
Synaptic Transmission
Intellectual Disability
Synapses
Genes
Embryonic Development
Opitz-Kaveggia syndrome
Exons
Proteins
Central Nervous System
Mutation
Brain

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Piluso, G., D'Amico, F., Saccone, V., Bismuto, E., Rotundo, I. L., Di Domenico, M., ... Nigro, V. (2008). A missense mutation in CASK causes FG syndrome in an Italian family. American Journal of Human Genetics, 84(2), 162-177. https://doi.org/10.1016/j.ajhg.2008.12.018

A missense mutation in CASK causes FG syndrome in an Italian family. / Piluso, Giulio; D'Amico, Francesca; Saccone, Valentina; Bismuto, Ettore; Rotundo, Ida Luisa; Di Domenico, Marina; Aurino, Stefania; Schwartz, Charles E.; Neri, Giovanni; Nigro, Vincenzo.

In: American Journal of Human Genetics, Vol. 84, No. 2, 08.08.2008, p. 162-177.

Research output: Contribution to journalArticle

Piluso, G, D'Amico, F, Saccone, V, Bismuto, E, Rotundo, IL, Di Domenico, M, Aurino, S, Schwartz, CE, Neri, G & Nigro, V 2008, 'A missense mutation in CASK causes FG syndrome in an Italian family', American Journal of Human Genetics, vol. 84, no. 2, pp. 162-177. https://doi.org/10.1016/j.ajhg.2008.12.018
Piluso, Giulio ; D'Amico, Francesca ; Saccone, Valentina ; Bismuto, Ettore ; Rotundo, Ida Luisa ; Di Domenico, Marina ; Aurino, Stefania ; Schwartz, Charles E. ; Neri, Giovanni ; Nigro, Vincenzo. / A missense mutation in CASK causes FG syndrome in an Italian family. In: American Journal of Human Genetics. 2008 ; Vol. 84, No. 2. pp. 162-177.
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