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 language | English |
|---|---|
| Pages (from-to) | 162-177 |
| Number of pages | 16 |
| Journal | American Journal of Human Genetics |
| Volume | 84 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Aug 8 2008 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
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 journal › Article
}
TY - JOUR
T1 - A missense mutation in CASK causes FG syndrome in an Italian family
AU - Piluso, Giulio
AU - D'Amico, Francesca
AU - Saccone, Valentina
AU - Bismuto, Ettore
AU - Rotundo, Ida Luisa
AU - Di Domenico, Marina
AU - Aurino, Stefania
AU - Schwartz, Charles E.
AU - Neri, Giovanni
AU - Nigro, Vincenzo
PY - 2008/8/8
Y1 - 2008/8/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=62649108006&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62649108006&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2008.12.018
DO - 10.1016/j.ajhg.2008.12.018
M3 - Article
C2 - 19200522
AN - SCOPUS:62649108006
VL - 84
SP - 162
EP - 177
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -