A partial MECP2 duplication in a mildly affected adult male: a putative role for the 3′ untranslated region in the MECP2 duplication phenotype
A partial MECP2 duplication in a mildly affected adult male: a putative role for the 3′ untranslated region in the MECP2 duplication phenotype
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DOI：
10.1186/1471-2350-13-71
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发表时间：
2012-08-10
影响因子：
--
通讯作者：
Cheung, Sau Wai
中科院分区：
文献类型：
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作者：
Hanchard, Neil A.;Carvalho, Claudia M. B.;Cheung, Sau Wai
背景资料：X连锁MECP 2基因的重复与中度至重度智力残疾、癫痫和男性神经精神疾病相关，而三重与更严重的表型相关。大多数携带者女性表现出完全偏斜的X-失活在外周血和一个明显的易感性特定的人格特质或neuropsychological symptoms.Methods：我们描述了一个谱系的临床表型分离重复的MECP 2发现临床阵列比较基因组杂交。使用多重连接依赖性探针扩增和荧光原位杂交，以及有针对性的高分辨率寡核苷酸微阵列分析和长距离PCR，从受影响的个人外周血样本中描绘的位置，大小和程度的重复。使用定量实时PCR，逆转录酶PCR，和蛋白质印迹analysis.Results：我们观察到一个成年男性癫痫和轻度神经认知功能障碍谁是能够独立运作的部分MECP 2重复的重排的分子后果进行了研究，这种表型以前没有被报道在MECP 2拷贝数的男性窝藏收益。这个人的女儿也遗传了同样的重复，她也患有神经认知障碍和癫痫，并携带了额外的拷贝数变异。重复片段涉及MECP 2的所有4个外显子，但排除了几乎整个3'非翻译区（UTR），基因组重排导致MECP 2-TEX 28融合基因mRNA转录本。MECP 2和由此产生的融合基因的表达增加都得到了证实，但是，从淋巴母细胞裂解物的蛋白质印迹分析表明增加MeCP 2蛋白没有证据的一个稳定的融合基因蛋白product.Conclusion：一个轻度受影响的成年男性与MECP 2的重复和父亲的这种重复传输的观察是独特的MECP 2的重复报道的情况下。临床和分子发现暗示了MECP 2复制综合征的完全神经认知表达的最小关键区域，并表明3' UTR在减轻疾病表型的严重性中的作用。
Background: Duplications of the X-linked MECP2 gene are associated with moderate to severe intellectual disability, epilepsy, and neuropsychiatric illness in males, while triplications are associated with a more severe phenotype. Most carrier females show complete skewing of X-inactivation in peripheral blood and an apparent susceptibility to specific personality traits or neuropsychiatric symptoms.Methods: We describe the clinical phenotype of a pedigree segregating a duplication of MECP2 found on clinical array comparative genomic hybridization. The position, size, and extent of the duplication were delineated in peripheral blood samples from affected individuals using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization, as well as targeted high-resolution oligonucleotide microarray analysis and long-range PCR. The molecular consequences of the rearrangement were studied in lymphoblast cell lines using quantitative real-time PCR, reverse transcriptase PCR, and western blot analysis.Results: We observed a partial MECP2 duplication in an adult male with epilepsy and mild neurocognitive impairment who was able to function independently; this phenotype has not previously been reported among males harboring gains in MECP2 copy number. The same duplication was inherited by this individual's daughter who was also affected with neurocognitive impairment and epilepsy and carried an additional copy-number variant. The duplicated segment involved all four exons of MECP2, but excluded almost the entire 3' untranslated region (UTR), and the genomic rearrangement resulted in a MECP2-TEX28 fusion gene mRNA transcript. Increased expression of MECP2 and the resulting fusion gene were both confirmed; however, western blot analysis of lysates from lymphoblast cells demonstrated increased MeCP2 protein without evidence of a stable fusion gene protein product.Conclusion: The observations of a mildly affected adult male with a MECP2 duplication and paternal transmission of this duplication are unique among reported cases with a duplication of MECP2. The clinical and molecular findings imply a minimal critical region for the full neurocognitive expression of the MECP2 duplication syndrome, and suggest a role for the 3' UTR in mitigating the severity of the disease phenotype.