Dataset Information

Skewed X-Chromosome Inactivation and Parental Gonadal Mosaicism Are Implicated in X-Linked Recessive Female Hemophilia Patients.

ABSTRACT:

Background

Hemophilia 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.

Methods

Three 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.

Results

All 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.

Conclusions

In 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.

SUBMITTER: Shen MC

PROVIDER: S-EPMC9600608 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Skewed X-Chromosome Inactivation and Parental Gonadal Mosaicism Are Implicated in X-Linked Recessive Female Hemophilia Patients.

Shen Ming-Ching MC Chang Shun-Ping SP Lee Dong-Jay DJ Lin Wen-Hsiang WH Chen Ming M Ma Gwo-Chin GC

Diagnostics (Basel, Switzerland) 20220920 10

<h4>Background</h4>Hemophilia 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.<h4>Methods</h4>Three families with female hemophilia patients, ...[more]

PMID: 36291957

Similar Datasets

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.

Dataset Information

Skewed X-Chromosome Inactivation and Parental Gonadal Mosaicism Are Implicated in X-Linked Recessive Female Hemophilia Patients.

Background

Methods

Results

Conclusions

Publications

Skewed X-Chromosome Inactivation and Parental Gonadal Mosaicism Are Implicated in X-Linked Recessive Female Hemophilia Patients.

Similar Datasets

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