一个轻度受影响的成年男性中存在 MECP2 部分重复：MECP2 重复表型中 3'非翻译区的潜在作用。
A partial MECP2 duplication in a mildly affected adult male: a putative role for the 3' untranslated region in the MECP2 duplication phenotype.
机构信息
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
出版信息
BMC Med Genet. 2012 Aug 10;13:71. doi: 10.1186/1471-2350-13-71.
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.
背景
X 连锁 MECP2 基因的重复与男性中度至重度智力障碍、癫痫和神经精神疾病有关，而三倍体则与更严重的表型有关。大多数携带女性在外周血中表现出完全的 X 染色体失活偏斜，并表现出对特定人格特质或神经精神症状的明显易感性。
方法
我们描述了一个家系的临床表型，该家系存在 MECP2 重复，该重复是在临床阵列比较基因组杂交中发现的。使用多重连接依赖性探针扩增和荧光原位杂交，以及靶向高分辨率寡核苷酸微阵列分析和长距离 PCR，在外周血样本中描绘了受影响个体中重复的位置、大小和范围。使用定量实时 PCR、逆转录 PCR 和 Western blot 分析研究了重排的分子后果。
结果
我们观察到一名患有癫痫和轻度神经认知障碍的成年男性存在部分 MECP2 重复，该男性能够独立生活；这种表型以前在携带 MECP2 拷贝数增益的男性中没有报道过。该个体的女儿也受到神经认知障碍和癫痫的影响，并携带额外的拷贝数变异，她继承了相同的重复。重复的片段涉及 MECP2 的所有四个外显子，但排除了几乎整个 3'非翻译区（UTR），基因组重排导致 MECP2-TEX28 融合基因 mRNA 转录本。均证实 MECP2 的表达增加以及由此产生的融合基因，但来自淋巴母细胞的裂解物的 Western blot 分析表明 MeCP2 蛋白增加，而没有稳定的融合基因蛋白产物的证据。
结论
患有 MECP2 重复的轻度成年男性和该重复的父系传递的观察结果在报道的 MECP2 重复病例中是独特的。临床和分子发现表明，MECP2 重复综合征的完整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程度方面发挥作用。
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