Lack of MECP2 gene transcription on the duplicated alleles of two related asymptomatic females with Xq28 duplications and opposite X-chromosome inactivation skewing.
Hum Mutat
; 42(11): 1429-1442, 2021 11.
Article
em En
| MEDLINE
| ID: mdl-34273908
ABSTRACT
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
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Cromossomos Humanos X
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Alelos
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Proteína 2 de Ligação a Metil-CpG
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Inativação do Cromossomo X
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Duplicação Cromossômica
Limite:
Adult
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Female
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Humans
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Infant
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Male
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Middle aged
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China