Santos-Rebouças Cíntia B, Boy Raquel, Vianna Evelyn Q, Gonçalves Andressa P, Piergiorge Rafael M, Abdala Bianca B, Dos Santos Jussara M, Calassara Veluma, Machado Filipe B, Medina-Acosta Enrique, Pimentel Márcia M G
Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
Front Genet. 2020 Mar 4;11:101. doi: 10.3389/fgene.2020.00101. eCollection 2020.
In mammalian females, X-chromosome inactivation (XCI) acts as a dosage compensation mechanism that equalizes X-linked genes expression between homo- and heterogametic sexes. However, approximately 12-23% of X-linked genes escape from XCI, being bi-allelic expressed. Herein, we report on genetic and functional data from an asymptomatic female of a Fragile X syndrome family, who harbors a large deletion on the X-chromosome. Array-CGH uncovered that the , terminal, paternally originated 32 Mb deletion on Xq25-q28 spans 598 RefSeq genes, including escape and variable escape genes. Androgen receptor () and retinitis pigmentosa 2 () methylation assays showed extreme skewed XCI ratios from both peripheral blood and buccal mucosa, silencing the abnormal X-chromosome. Surprisingly, transcriptome-wide analysis revealed that escape and variable escape genes spanning the deletion are mostly upregulated on the active X-chromosome, precluding major clinical/cognitive phenotypes in the female. Metaphase high count, hemizygosity concordance for microsatellite markers, and monoallelic expression of genes within the deletion suggest the absence of mosaicism in both blood and buccal mucosa. Taken together, our data suggest that an additional protective gene-by-gene mechanism occurs at the transcriptional level in the active X-chromosome to counterbalance detrimental phenotype effects of large Xq deletions.
在哺乳动物雌性中，X染色体失活（XCI）作为一种剂量补偿机制，使同配性别和异配性别之间的X连锁基因表达达到平衡。然而，约12% - 23%的X连锁基因逃避XCI，呈双等位基因表达。在此，我们报告了一个脆性X综合征家族中一名无症状女性的遗传和功能数据，该女性X染色体上存在一个大的缺失。阵列比较基因组杂交（Array-CGH）发现，Xq25 - q28上源自父方的32 Mb末端缺失跨越598个RefSeq基因，包括逃避和可变逃避基因。雄激素受体（AR）和视网膜色素变性2（RP2）甲基化分析显示，外周血和颊黏膜的XCI比例严重偏斜，使异常的X染色体失活。令人惊讶的是，全转录组分析表明，跨越该缺失的逃避和可变逃避基因大多在活跃的X染色体上上调，这排除了该女性出现主要临床/认知表型的可能性。中期高计数、微卫星标记的半合子一致性以及缺失区域内基因的单等位基因表达表明，血液和颊黏膜中均不存在嵌合体现象。综上所述，我们的数据表明，在活跃的X染色体转录水平上存在一种额外的逐基因保护机制，以抵消Xq大缺失的有害表型效应。
