scholarly journals A Functional Mutation in HDAC8 Gene as Novel Diagnostic Marker for Cornelia De Lange Syndrome

2018 ◽  
Vol 47 (6) ◽  
pp. 2388-2395 ◽  
Author(s):  
Xueren Gao ◽  
Zhuo Huang ◽  
Yanjie Fan ◽  
Yu Sun ◽  
Huili Liu ◽  
...  
Keyword(s):  
Missense Mutation ◽  
X Chromosome ◽  
Genetic Disorder ◽  
Sodium Dodecyl ◽  
Pathogenic Mutation ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Cornelia De Lange Syndrome ◽  
Cornelia De Lange

Background/Aims: Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder classically characterized by distinctive facies, growth retardation, intellectual disability, feeding difficulties, and multiple organ system anomalies. Previously, the diagnosis of CdLS was based mainly on identifying the typical phenotype in patients. However, with the advances in clinical molecular genetic diagnostic techniques, more patients, especially patients with milder phenotypes, are being diagnosed from detecting pathogenic mutation. Methods: Pathogenic mutation in a female patient with a milder phenotype was detected using whole-exome sequencing (WES), and was further characterized using bioinformatic analysis and in vitro functional experiments, including X-chromosome inactivation analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and enzyme activity assay. Results: This patient was found to harbor a novel missense mutation (c.806T>G, p.I269R) in the coding region of the HDAC8 gene, which was predicted to be pathogenic. Compared with other CdLS patients with HDAC8 mutation, the patient lacked typical facies, including synophrys and arched eyebrows. In vitro functional experiments showed the presence of skewed X-chromosome inactivation. Furthermore, the novel mutation decreased the dissolubility and enzymatic activity of HDAC8 protein. Conclusions: The present study identified a novel missense mutation (c.806T>G, p.I269R) in the HDAC8 gene leading to CdLS, which not only provided strong evidence for diagnosis in this present patient, but also expanded the spectrum of pathogenic mutations for CdLS.

X–chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro

Nature ◽  
1978 ◽  
Vol 271 (5643) ◽  
pp. 329-333 ◽  
Author(s):  
Gail R. Martin ◽  
Charles J. Epstein ◽  
Bruce Travis ◽  
Georgianne Tucker ◽  
Shaul Yatziv ◽  
...  
Keyword(s):  
Stem Cells ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation

scholarly journals Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization

2016 ◽  
Vol 113 (12) ◽  
pp. 3197-3202 ◽  
Author(s):  
Kun Tan ◽  
Lei An ◽  
Kai Miao ◽  
Likun Ren ◽  
Zhuocheng Hou ◽  
...  
Keyword(s):  
In Vitro Fertilization ◽  
Sex Ratio ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Epigenetic Modifications ◽  
Chromosome Inactivation ◽  
Developmental Defects ◽  
Vitro Fertilization ◽  
Preimplantation Stage

Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short- or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards, was reported in bovine and porcine embryos and even human IVF newborns. However, since the first case of sex skewing reported in 1991, the underlying mechanisms remain unclear. We reported herein that sex ratio is skewed in mouse IVF offspring, and this was a result of female-biased peri-implantation developmental defects that were originated from impaired imprinted X chromosome inactivation (iXCI) through reduced ring finger protein 12 (Rnf12)/X-inactive specific transcript (Xist) expression. Compensation of impaired iXCI by overexpression of Rnf12 to up-regulate Xist significantly rescued female-biased developmental defects and corrected sex ratio in IVF offspring. Moreover, supplementation of an epigenetic modulator retinoic acid in embryo culture medium up-regulated Rnf12/Xist expression, improved iXCI, and successfully redeemed the skewed sex ratio to nearly 50% in mouse IVF offspring. Thus, our data show that iXCI is one of the major epigenetic barriers for the developmental competence of female embryos during preimplantation stage, and targeting erroneous epigenetic modifications may provide a potential approach for preventing IVF-associated complications.

scholarly journals Human X chromosome inactivation and reactivation: implications for cell reprogramming and disease

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160358 ◽  
Author(s):  
Irene Cantone ◽  
Amanda G. Fisher
Keyword(s):  
Cell Fusion ◽  
X Chromosome ◽  
Expression Profiles ◽  
Es Cells ◽  
Human Fibroblasts ◽  
Embryonic Stem ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation

X-chromosome inactivation (XCI) is an exemplar of epigenetic regulation that is set up as pluripotent cells differentiate. Once established, XCI is stably propagated, but can be reversed in vivo or by pluripotent reprogramming in vitro . Although reprogramming provides a useful model for inactive X (Xi) reactivation in mouse, the relative instability and heterogeneity of human embryonic stem (ES) cells and induced pluripotent stem cells hampers comparable progress in human. Here we review studies aimed at reactivating the human Xi using different reprogramming strategies. We outline our recent results using mouse ES cells to reprogramme female human fibroblasts by cell–cell fusion. We show that pluripotent reprogramming induces widespread and rapid chromatin remodelling in which the human Xi loses XIST and H3K27m3 enrichment and selected Xi genes become reactivated, ahead of mitotic division. Using RNA sequencing to map the extent of human Xi reactivation, and chromatin-modifying drugs to potentiate reactivation, we outline how this approach could be used to better design strategies to re-express human X-linked loci. As cell fusion induces the expression of human pluripotency genes that represent both the ‘primed’ and ‘naive’ states, this approach may also offer a fresh opportunity to segregate human pluripotent states with distinct Xi expression profiles, using single-cell-based approaches. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

scholarly journals Xmas ESC: A new female embryonic stem cell system that reveals the BAF complex as a key regulator of the establishment of X chromosome inactivation

2019 ◽  
Author(s):  
Andrew Keniry ◽  
Natasha Jansz ◽  
Linden J. Gearing ◽  
Iromi Wanigasuriya ◽  
Joseph Chen ◽  
...  
Keyword(s):  
X Chromosome ◽  
Embryonic Stem ◽  
X Chromosome Inactivation ◽  
Cell System ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Baf Complex ◽  
Specific Process ◽  
Female Specific

SummaryAlthough female pluripotency significantly differs to male, complications with in vitro culture of female embryonic stem cells (ESC) have severely limited the use and study of these cells. We report a replenishable female ESC system, Xmas, that has enabled us to optimise a protocol for preserving the XX karyotype. Our protocol also improves male ESC fitness. We utilised our Xmas ESC system to screen for regulators of the female-specific process of X chromosome inactivation, revealing chromatin remodellers Smarcc1 and Smarca4 as key regulators of establishment of X inactivation. The remodellers create a nucleosome depleted region at gene promotors on the inactive X during exit from pluripotency, without which gene silencing fails. Our female ESC system provides a tractable model for XX ESC culture that will expedite study of female pluripotency and has enabled us to discover new features of the female-specific process of X inactivation.

scholarly journals A novel approach to differentiate rat embryonic stem cells in vitro reveals a role for RNF12 in activation of X chromosome inactivation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Aristea Magaraki ◽  
Agnese Loda ◽  
Cristina Gontan ◽  
Sarra Merzouk ◽  
Esther Sleddens-Linkels ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
X Chromosome ◽  
Embryonic Stem ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Novel Approach

scholarly journals Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients—Lessons from Wide Genome Analyses

2021 ◽  
Vol 22 (16) ◽  
pp. 9074
Author(s):  
Rima Dardik ◽  
Einat Avishai ◽  
Shadan Lalezari ◽  
Assaf A. Barg ◽  
Sarina Levy-Mendelovich ◽  
...  
Keyword(s):  
X Chromosome ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Bioinformatic Analysis ◽  
Pathogenic Mutation ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Chromosome Inactivation ◽  
Pcr Analysis ◽  
Two Generations

Introduction: Hemophilia A (HA) is an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency or dysfunction due to F8 gene mutations. HA carriers are usually asymptomatic because their FVIII levels correspond to approximately half of the concentration found in healthy individuals. However, in rare cases, a carrier may exhibit symptoms of moderate to severe HA primarily due to skewed inactivation of her non-hemophilic X chromosome. Aim: The aim of the study was to investigate X-chromosome inactivation (XCI) patterns in HA carriers, with special emphasis on three karyotypically normal HA carriers presenting with moderate to severe HA phenotype due to skewed XCI, in an attempt to elucidate the molecular mechanism underlying skewed XCI in these symptomatic HA carriers. The study was based on the hypothesis that the presence of a pathogenic mutation on the non-hemophilic X chromosome is the cause of extreme inactivation of that X chromosome. Methods: XCI patterns were studied by PCR analysis of the CAG repeat region in the HUMARA gene. HA carriers that demonstrated skewed XCI were further studied by whole-exome sequencing (WES) followed by X chromosome-targeted bioinformatic analysis. Results: All three HA carriers presenting with the moderate to severe HA phenotype due to skewed XCI were found to carry pathogenic mutations on their non-hemophilic X chromosomes. Patient 1 was diagnosed with a frameshift mutation in the PGK1 gene that was associated with familial XCI skewing in three generations. Patient 2 was diagnosed with a missense mutation in the SYTL4 gene that was associated with familial XCI skewing in two generations. Patient 3 was diagnosed with a nonsense mutation in the NKAP gene that was associated with familial XCI skewing in two generations. Conclusion: Our results indicate that the main reason for skewed XCI in our female HA patients was negative selection against cells with a disadvantage caused by an additional deleterious mutation on the silenced X chromosome, thus complicating the phenotype of a monogenic X-linked disease. Based on our study, we are currently offering the X inactivation test to symptomatic hemophilia carriers and plan to expand this approach to symptomatic carriers of other X-linked diseases, which can be further used in pregnancy planning.

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