Piluso Giulio, D'Amico Francesca, Saccone Valentina, Bismuto Ettore, Rotundo Ida Luisa, Di Domenico Marina, Aurino Stefania, Schwartz Charles E, Neri Giovanni, Nigro Vincenzo
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Napoli 80138, Italy.
Am J Hum Genet. 2009 Feb;84(2):162-77. doi: 10.1016/j.ajhg.2008.12.018. Epub 2009 Feb 5.
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.
FG综合征（FGS）于1974年首次被描述，是一种X连锁的多发性先天性异常/智力障碍（MCA/MR）疾病，其临床变异性高且具有遗传异质性。到目前为止，X染色体上已有五个位点（FGS1 - 5）与该表型相关，但迄今为止仅鉴定出一个基因MED12。该基因的突变仅导致数量有限的FGS患者出现一种更具特征性的表型，即Opitz - Kaveggia表型。我们在此报告，CASK基因中的一个p.R28L（c.83G→T）错义突变在一个先前被定位到Xp11.4 - p11.3（FGS4）的意大利家族中导致了FGS表型。所鉴定的错义突变与该家族中的表型共分离，并且在1000条相同种族来源的对照X染色体中不存在。对CASK蛋白功能的广泛分析以及通过分子动力学（MD）模拟进行的结构和动力学研究并未揭示p.R28L替代所诱导的显著改变。然而，我们观察到CASK的外显子2部分跳跃，推测这是由c.83G→T颠换诱导的外显子剪接增强子（ESE）识别不当的结果。CASK是一种多结构域支架蛋白，在中枢神经系统（CNS）中高度表达，并特异性定位于突触，在那里它形成调节神经传递的大型信号复合物。我们认为观察到的表型很可能是胚胎发生、脑发育和分化过程中CASK表达谱改变的结果。
