First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation.
Rett综合征是一种X连锁神经发育障碍，可导致严重智力障碍和运动残疾，每10000至15000名活产女婴中约有1例患病。该疾病的特点是在6至18个月龄前发育似乎正常，随后运动和沟通能力出现倒退，这是由X连锁MECP2基因突变所致，该基因编码甲基CpG结合蛋白2。本研究通过全面的基因测序进行分子分析，发现了一个不寻常的新发双重突变（c.695 G > T；c.880C > T），该突变位于MECP2基因的高度保守区域，影响MeCP2蛋白的转录抑制结构域（TRD），并首次导致Rett综合征的严重表型。此外，对MECP2突变的计算研究显示，新发突变c.695 G > T具有高度有害性，可影响MeCP2蛋白，同时也对MECP2基因表达产生不良影响，并导致MECP2结构折叠受影响及稳定性降低。因此，改变的TRD结构域引发了MECP2功能的破坏过程。因此，这是首项在北非地区Rett综合征严重临床表型患者中突出报道MeCP2蛋白转录抑制结构域（TRD）新发双重突变的研究。
Rett syndrome is an X-linked neurodevelopmental disorder that develops a profound intellectual and motor disability and affects 1 from 10 000 to 15 000 live female births. This disease is characterized by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress which is caused by mutations occurred in the X-linked MECP2 gene, encoding the methyl-CpG binding protein 2. This research study reports a molecular analysis via an exhaustive gene sequencing which reveals an unusual novel double mutation (c.695 G > T; c.880C > T) located in a highly conserved region in MECP2 gene affecting the transcription repression domain (TRD) of MeCP2 protein and leading for the first time to a severe phenotype of Rett syndrome. Moreover, a computational investigation of MECP2 mutations demonstrates that the novel mutation c.695 G > T is highly deleterious which affects the MeCP2 protein showing also an adverse impact on MECP2 gene expression and resulting in an affected folding and decreased stability of MECP2 structures. Thus, the altered TRD domain engenders a disrupted process of MECP2 functions. Therefore, this is the first study which highlights a novel double mutation among the transcription repression domain (TRD) of MeCP2 protein in Rett patient with a severe clinical phenotype in North Africa region.
Rania Ghorbel, Raouia Ghorbel, Aida Rouissi, Nourhene Fendri-Kriaa, Ghada Ben Salah, Neila Belguith, et al. First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation.. Biochemical and biophysical research communications. 2018; doi:10.1016/j.bbrc.2018.02.029.
Rania Ghorbel, Raouia Ghorbel, Aida Rouissi, Nourhene Fendri-Kriaa, Ghada Ben Salah, Neila Belguith, et al (2018). First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation.. Biochemical and biophysical research communications. https://doi.org/10.1016/j.bbrc.2018.02.029
Rania Ghorbel, Raouia Ghorbel, Aida Rouissi, Nourhene Fendri-Kriaa, Ghada Ben Salah, Neila Belguith, et al. First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation.[J]. Biochemical and biophysical research communications, 2018 doi:10.1016/j.bbrc.2018.02.029.
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