期刊
HUMAN MUTATION
卷 42, 期 11, 页码 1429-1442出版社
WILEY
DOI: 10.1002/humu.24262
关键词
allele-specific expression (ASE); androgen receptor (AR) assay; MECP2 duplication; RNA sequencing; skewed X-chromosome inactivation (XCI)
资金
- National Natural Science Foundation of China [81801441]
- Key Research and Development Program of the Zhejiang Province [2019C03025]
- Medical Health Science and Technology Project of Zhejiang Provincial Health Commission [2021KY772]
- Public Welfare Technology Research Program of Zhejiang Province [LGC20H200003]
Xq28 duplication syndrome is a severe neurodevelopmental disorder in males due to MeCP2 overexpression, while females with MECP2 duplication are usually asymptomatic carriers due to skewed X-chromosome inactivation. The study of two asymptomatic females showed that RNA sequencing can be more relevant for establishing the clinical phenotype of MECP2 duplication in females, suggesting additional inhibition mechanisms at the transcriptional level may counterbalance the detrimental effects of the duplication.
Xq28 duplication syndrome (MIM# 300815) is a severe neurodevelopmental disorder in males due to MeCP2 overexpression. Most females with MECP2 duplication are asymptomatic carriers, but there are phenotypic heterogeneities. Skewed X-chromosome inactivation (XCI) can protect females from exhibiting clinical phenotypes. Herein we reported two asymptomatic females (mother and grandmother) with interstitial Xq28 duplication. AR and RP2 assays showed that both had extremely skewed XCI, the Xq28 duplicated chromosome was inactivated in the mother, but was surprisingly activated in the grandmother. Interestingly, by combining RNA sequencing and whole-exome sequencing, we confirmed that XIST only expressed in the Xq28 duplication chromosomes of the two females, indicating that the Xq28 duplication chromosomes were inactive. Meanwhile, MECP2 and most XCI genes in the duplicated X-chromosomes were not transcriptionally expressed or upregulated, precluding major clinical phenotypes in the two females, especially the grandmother. We showed that XCI status detected using RNA sequencing was more relevant for establishing the clinical phenotype of MECP2 duplication in females. It suggested that there were other factors maintaining the XCI status in addition to DNA methylation, a possible additional inhibition mechanism occurred at the transcriptional level in the unmethylated X-chromosome, counter balancing the MECP2 duplication's detrimental phenotype effects.
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