Persistence of skewed X-chromosome inactivation in pre-B acute lymphoblastic leukemia of a female ATRX mutation carrier.
Ontology highlight
ABSTRACT:
SUBMITTER: Bradley CP
PROVIDER: S-EPMC6737413 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
Publications
Persistence of skewed X-chromosome inactivation in pre-B acute lymphoblastic leukemia of a female ATRX mutation carrier.
Bradley Christian P CP Chen Cai C Oetjen Karolyn A KA Yan Cheng C Panjwani Reema R Hauffe Sara S Calvo Katherine R KR Yuan Constance C Patel Prapti Arvind PA Montgomery Nathan D ND Foster Matthew C MC Battiwalla Minoo M Barrett A John AJ Gibbons Richard J RJ Ito Sawa S
Blood advances 20190901 17
Similar Datasets
Project description:In this study, we report on a family with X-linked dyskeratosis congenita (DC). Linkage analysis with markers in the factor VIII gene at Xq28 yielded a LOD score of 2 at a recombination of 0. Clinical manifestations of DC, such as skin lesions following the Blaschko lines, were present in two obligate carrier females. Highly skewed X inactivation was observed in white blood cells, cultured skin fibroblasts, and buccal mucosa from female carriers of DC in this family. This suggests a critical role for the DC gene in bone marrow-cell and fibroblast-cell proliferation.
| S-EPMC1712491 | biostudies-other
Project description:BackgroundX chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with X-linked gene dosage and the choice of X chromosome silencing in female cells. Previous studies demonstrated that sex chromosome aneuploidies may be related to the pathogeneses of some psychiatric diseases. Here, we examined the changes in skewed XCI in patients with schizophrenia.MethodsA total of 109 female schizophrenia (SCZ) patients and 80 age- and sex-matched healthy controls (CNTLs) were included in this study. We evaluated clinical features including disease onset age, disease duration, clinical symptoms by the Positive and Negative Syndrome Scale (PANSS) and antipsychotic treatment dosages. The XCI skewing patterns were analyzed by the methylation profile of the HUMARA gene found in DNA isolated from SCZ patient and CNTL leukocytes in the three age groups.ResultsFirst, we found that the frequency of skewed XCI in SCZ patients was 4 times more than that in the age- and sex-matched CNTLs (p < 0.01). Second, we found an earlier onset of severe XCI skewing in the SCZ patients than in CNTLs. Third, we demonstrated a close relationship between the severity of skewed XCI and schizophrenic symptoms (PANSS score ≥ 90) as well as the age of disease onset. Fourth, we demonstrated that the skewed XCI in SCZ patients was not transmitted from the patients' mothers.LimitationsThe XCI skewing pattern might differ depending on tissues or organs. Although this is the first study to explore skewed XCI in SCZ, in the future, samples from different tissues or cells in SCZ patients might be important for understanding the impact of skewed XCI in this disease.ConclusionOur study, for the first time, investigated skewed XCI in female SCZ patients and presented a potential mechanism for the sex differences in SCZ. Our data also suggested that XCI might be a potential target for the development of female-specific interventions for SCZ.
| S-EPMC7368719 | biostudies-literature
Project description:Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.
| S-EPMC10764769 | biostudies-literature
Project description:ObjectivesHemophilia A (HA) is an X-linked recessive inherited bleeding disorder that typically affects men. Women are usually asymptomatic carriers, and rarely presenting with severe or moderately severe phenotype. This study aims to describe a case of a 17-year-old girl with moderate HA, investigating the mechanisms of her condition and the genetic basis within her family.MethodsWe conducted coagulation tests and bleeding assessments to evaluate her bleeding phenotype. Molecular genetic examinations, karyotype analysis, X-chromosome inactivation testing, and targeted bioinformatic analysis were used to identify potential genetic etiologies.ResultsThe proband exhibited a severe bleeding phenotype and was found to be a heterozygous carrier of an intron 22 inversion (Inv22) with a normal chromosomal karyotype. No other hemostatic defects were identified through whole exome sequencing. The proband's mother and monozygotic twin sister are also Inv22 carriers, yet remain asymptomatic with normal FVIII activity. X-chromosome inactivation experiments revealed unbalanced inactivation in the proband, leading to the silencing of the healthy X copy. Notably, several novel X-linked gene mutations (SHROOM2, RPGR, VCX3B, GAGE, GCNA, ZNF280C, CT45A, and XK) were identified in the proband compared to her monozygotic twin sister, though their impact on X-chromosome inactivation remains unclear.ConclusionOur findings suggest that the proband's bleeding phenotype results from unbalanced X-chromosome inactivation. This research marks the first analysis of X chromosome-related gene mutations among monozygotic twins who are carriers of hemophilia A, laying the groundwork for further investigations into the disorder's pathogenesis in women and highlighting the complexities in genetic counseling.
| S-EPMC11743268 | biostudies-literature
Project description:BackgroundHemophilia A (HA) and B (HB) are X-linked recessive disorders that mainly affect males born from a mother carrier. Females are rarely affected but a number of mechanisms have been suggested in symptomatic females, such as skewed X-chromosome inactivation (XCI), chromosomal rearrangements, and hermaphrodites. Different methodologies are required to elucidate the underlying causes of such diseases in female patients.MethodsThree families with female hemophilia patients, including two HA and one HB, were enrolled for genetic analyses. Cytogenetics, molecular examinations on F8 and F9 genes, XCI assay, and linkage analysis were performed.ResultsAll three female patients are demonstrated to be heterozygous for an F8, or F9 mutation: one patient is inherited from her unaffected mother and the other two are sporadic cases. All three patients exhibit skewed XCI. The inherited patient is found to be unmethylated in the maternal X chromosome, which increases the potential for the expression of the mutant allele. The two sporadic cases are hypomethylated or unmethylated in the paternal X chromosome, suggesting that paternal gonadal mosaicism may exist in these families.ConclusionsIn addition to screening for coagulation function, different genetic analyses are mandatory to explore the nature of mechanisms responsible for the X-linked recessive disorders in female patients as shown in this study. Our results confirm that skewed XCI is responsible for hemophilia in heterozygous female patients. Likewise, our results implicate that parental gonadal mosaicism, followed by skewed XCI, contributes to hemophilia in "sporadic" female patients.
| S-EPMC9600608 | biostudies-literature
Project description:X chromosome inactivation (XCI) is a mechanism specifically initiated in female cells to silence one X chromosome, thereby equalizing the dose of X-linked gene products between male and female cells. XCI is regulated by a locus on the X chromosome termed the X-inactivation centre (XIC). Located within the XIC is XIST, which acts as a master regulator of XCI. During XCI, XIST is upregulated on the inactive X chromosome and chromosome-wide cis spreading of XIST leads to inactivation. In mouse, the Xic comprises Xist and all cis-regulatory elements and genes involved in Xist regulation. The activity of the XIC is regulated by trans-acting factors located elsewhere in the genome: X-encoded XCI activators positively regulating XCI, and autosomally encoded XCI inhibitors providing the threshold for XCI initiation. Whether human XCI is regulated through a similar mechanism, involving trans-regulatory factors acting on the XIC has remained elusive so far. Here, we describe a female individual with ovarian dysgenesis and a small X chromosomal deletion of the XIC. SNP-array and targeted locus amplification (TLA) analysis defined the deletion to a 1.28 megabase region, including XIST and all elements and genes that perform cis-regulatory functions in mouse XCI. Cells carrying this deletion still initiate XCI on the unaffected X chromosome, indicating that XCI can be initiated in the presence of only one XIC. Our results indicate that the trans-acting factors required for XCI initiation are located outside the deletion, providing evidence that the regulatory mechanisms of XCI are conserved between mouse and human.This article is part of the themed issue 'X-chromosome inactivation: a tribute to Mary Lyon'.
| S-EPMC5627161 | biostudies-literature
Project description:X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.
| S-EPMC6460563 | biostudies-literature
Project description:X-chromosome inactivation (XCI) is the process in which one of the two copies of the X-chromosome in females is randomly inactivated to achieve the dosage compensation of X-linked genes between males and females. That is, 50% of the cells have one allele inactive and the other 50% of the cells have the other allele inactive. However, studies have shown that skewed or nonrandom XCI is a biological plausibility wherein more than 75% of cells have the same allele inactive. Also, some of the X-chromosome genes escape XCI, i.e., both alleles are active in all cells. Current statistical tests for X-chromosome association studies can either account for random XCI (e.g., Clayton's approach) or escape from XCI (e.g., PLINK software). Because the true XCI process is unknown and differs across different regions on the X-chromosome, we proposed a unified approach of maximizing likelihood ratio over all biological possibilities: random XCI, skewed XCI, and escape from XCI. A permutation-based procedure was developed to assess the significance of the approach. We conducted simulation studies to compare the performance of the proposed approach with Clayton's approach and PLINK regression. The results showed that the proposed approach has higher powers in the scenarios where XCI is skewed while losing some power in scenarios where XCI is random or XCI is escaped, with well-controlled type I errors. We also applied the approach to the X-chromosomal genetic association study of head and neck cancer.
| S-EPMC4127090 | biostudies-literature
Project description:BackgroundHemophilia carriers occasionally present with bleeding tendency due to skewed inactivation of normal F8 carrying X chromosome.Key clinical questionCan extreme skewing of X-chromosome inactivation (XCI) with trisomy X cause low factor (F) VIII activity and bleeding in a hemophilia carrier?.Clinical approachA young female with low FVIII activity (2 IU/dL), who presented with history of frequent bleeding and F8 variant, NP_000123.1:p.(Arg1800His), was identified. The mother was also confirmed genetically as hemophilia carrier. Karyotype was 47, XXX, multiplex ligation-dependent probe amplification for aneuploidy in the family identified trisomy X only in the index case. Digital polymerase chain reaction using leucocytes, urine, and oral mucosa identified one maternal F8 variant carrying and 2 wild-type F8 carrying X chromosomes, but it detected no somatic mosaicisms. Methylation-sensitive-HpaII-polymerase chain reaction assay showed predominantly activated maternal and 2 fully inactivated paternal X chromosomes. The XCI patterns using tissues of different developmental origins showed extremely skewed XCI.ConclusionExtreme skewing of XCI can occur even in hemophilia carriers with trisomy X, conferring frequent bleeding and low FVIII activity.
| S-EPMC10704502 | biostudies-literature
Project description:Deficiency in ELF4, X-linked (DEX) is a newly identified monogenic autoinflammatory disease. Most reported cases are male, leading to the recognition of DEX being primarily limited to male patients. Here we described 3 pediatric female patients with DEX from 3 unrelated families, who are all heterozygous for ELF4 mutations (c.320_c.321insA, c.329delA and c.685 A > G). Similar to reported male DEX patients, the main clinical features include recurring oral ulcers, abdominal pain and diarrhea with colonoscopy showing ulcers in the colon. Meanwhile, novel and effective treatment strategies, such as the use of the biologic vedolizumab and exclusive enteral nutrition (EEN), have provided additional options for the treatment of DEX. Finally, we observed skewed X chromosome inactivation patterns in all three female patients, with over-inactivation of the X chromosome carrying the wild-type allele confirmed in two of them.
| S-EPMC11842529 | biostudies-literature