Saxena A, de Lagarde D, Leonard H, Williamson S L, Vasudevan V, Christodoulou J, Thompson E, MacLeod P, Ravine D
Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Level 2, North Block, Perth 6000, WA, Australia.
J Med Genet. 2006 Jun;43(6):470-7. doi: 10.1136/jmg.2005.036244. Epub 2005 Sep 9.
Rett syndrome (RTT) is an X linked neuro-developmental disorder affecting mostly girls. Mutations in the coding region of MECP2 are found in 80% of classic RTT patients. Until recently, the region encoding MECP2 was believed to comprise exons 2, 3, and 4 with the ATG start site located at the end of exon 2 (MeCP2_e2).
Recent reports of another mRNA transcript transcribed from exon 1 (MeCP2_e1) prompted us to screen exon 1 among RNA samples from 20 females with classic or atypical RTT.
A previously reported 11 base pair deletion in exon 1 was detected in one subject with a milder phenotype. Although RNA expression for both protein isoforms was detected from the mutant allele, evaluation of MeCP2 protein in uncultured patient lymphocytes by immunocytochemistry revealed that MeCP2 protein production was restricted to only 74-76% of lymphocytes. X chromosome inactivation studies of genomic DNA revealed similar XCI ratios at the HUMARA locus (73:27 with HpaII and 74:26 with McrBC). We have demonstrated that translation but not transcription of the MeCP2_e2 isoform is ablated by the 11 nucleotide deletion, 103 nucleotides upstream of the e2 translation start site.
These findings reveal that nucleotides within the deleted sequence in the 5'-UTR of the MeCP2_e2 transcript, while not required for transcription, are essential for translation.
雷特综合征（RTT）是一种X连锁神经发育障碍，主要影响女孩。80%的典型RTT患者在MECP2编码区存在突变。直到最近，人们一直认为编码MECP2的区域由外显子2、3和4组成，ATG起始位点位于外显子2末端（MeCP2_e2）。
最近有报道称从外显子1转录出另一种mRNA转录本（MeCP2_e1），这促使我们在20名患有典型或非典型RTT的女性的RNA样本中筛选外显子1。
在一名表型较轻的患者中检测到先前报道的外显子1中11个碱基对的缺失。尽管从突变等位基因中检测到了两种蛋白质异构体的RNA表达，但通过免疫细胞化学对未培养的患者淋巴细胞中的MeCP2蛋白进行评估发现，MeCP2蛋白的产生仅局限于74 - 76%的淋巴细胞。对基因组DNA的X染色体失活研究显示，在HUMARA位点的XCI比率相似（用HpaII酶切时为73:27，用McrBC酶切时为74:26）。我们已经证明，MeCP2_e2异构体的翻译而非转录因11个核苷酸的缺失而被消除，该缺失位于e2翻译起始位点上游103个核苷酸处。
这些发现表明，MeCP2_e2转录本5'-UTR中缺失序列内的核苷酸虽然不是转录所必需的，但对翻译至关重要。
