Showing papers on "Skewed X-inactivation published in 2021"

Gender Specific Differences in Disease Susceptibility: The Role of Epigenetics

Abstract: Many complex traits or diseases, such as infectious and autoimmune diseases, cancer, xenobiotics exposure, neurodevelopmental and neurodegenerative diseases, as well as the outcome of vaccination, show a differential susceptibility between males and females. In general, the female immune system responds more efficiently to pathogens. However, this can lead to over-reactive immune responses, which may explain the higher presence of autoimmune diseases in women, but also potentially the more adverse effects of vaccination in females compared with in males. Many clinical and epidemiological studies reported, for the SARS-CoV-2 infection, a gender-biased differential response; however, the majority of reports dealt with a comparable morbidity, with males, however, showing higher COVID-19 adverse outcomes. Although gender differences in immune responses have been studied predominantly within the context of sex hormone effects, some other mechanisms have been invoked: cellular mosaicism, skewed X chromosome inactivation, genes escaping X chromosome inactivation, and miRNAs encoded on the X chromosome. The hormonal hypothesis as well as other mechanisms will be examined and discussed in the light of the most recent epigenetic findings in the field, as the concept that epigenetics is the unifying mechanism in explaining gender-specific differences is increasingly emerging.

X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis

Abstract: Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where it is of approximately 1:4000. Clinical symptoms include angiokeratomas, corneal dystrophy, and neurological, cardiac and kidney involvement. The prevalence of symptomatic female carriers is about 70%, and in some cases, they can exhibit a severe phenotype. Previous studies suggest a correlation between skewed X chromosome inactivation and symptoms in carriers of X-linked disease, including Fabry disease. In this review, we briefly summarize the disease, focusing on the clinical symptoms of carriers and analysis of the studies so far published in regards to X chromosome inactivation pattern, and manifesting Fabry carriers. Out of 151 records identified, only five reported the correlation between the analysis of XCI in leukocytes and the related phenotype in Fabry carriers, in particular evaluating the Mainz Severity Score Index or cardiac involvement. The meta-analysis did not show any correlation between MSSI or cardiac involvement and skewed XCI, likely because the analysis of XCI in leukocytes is not useful for predicting the phenotype in Fabry carriers.

Novel exon-skipping variant disrupting the basic domain of HCFC1 causes intellectual disability without metabolic abnormalities in both male and female patients.

Abstract: HCFC1, a global transcriptional regulator, has been shown to associate with MMACHC expression Pathogenic variants in HCFC1 cause X-linked combined methylmalonic acidemia and hyperhomocysteinemia, CblX type (MIM# 309541) Recent studies showed that certain variants in HCFC1 are associated with X-linked intellectual disability with mild or absent metabolic abnormalities Here, we report five subjects (three males, two females) from the same family with a novel predicted loss of function HCFC1 variant All five patients exhibit developmental delay or intellectual disability/learning difficulty and some dysmorphic features; findings were milder in the female as compared to male subjects Biochemical studies in all patients did not show methylmalonic acidemia or hyperhomocysteinemia but revealed elevated vitamin B12 levels Trio exome sequencing of the proband and his parents revealed a maternally inherited novel variant in HCFC1 designated as c1781_1803 + 3del26insCA (NM_005334) Targeted testing confirmed the presence of the same variant in two half-siblings and maternal great uncle In silico analysis showed that the variant is expected to reduce the quality of the splice donor site in intron 10 and causes abnormal splicing Sequencing of proband's cDNA revealed exon 10 skipping Further molecular studies in the two manifesting females revealed moderate and high skewing of X inactivation Our results support previous observation that HCFC1 variants located outside the Kelch domain exhibit dissociation of the clinical and biochemical phenotype and cause milder or no metabolic changes We also show that this novel variant can be associated with a phenotype in females, although with milder severity, but further studies are needed to understand the role of skewed X inactivation among females in this rare disorder Our work expands the genotypes and phenotypes associated with HCFC1-related disorder

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

Abstract: 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.

Bayesian modeling of skewed X inactivation in genetically diverse mice identifies a novel Xce allele associated with copy number changes.

Abstract: Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176-kb candidate interval. A series of functional Xce alleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function structure basis and location of the Xce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross (CC) strains. Using published sequence data and applying a Bayesian "Polya urn" model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20-30 cells contributing to brain. Second, CC founder strain NOD/ShiLtJ has a novel and unique functional allele, Xceg, that is the weakest in the Xce allelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xceb), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within the Xce. Copy number variation is common at the Xce locus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weak Xce alleles.

Genetics, X-Linked Inheritance

Abstract: The X chromosome contains 867 identified genes; most of these genes are responsible for the development of tissues like bone, neural, blood, hepatic, renal, retina, ears, ear, cardiac, skin, and teeth. There are at least 533 disorders due to the involvement of the genes on the X chromosome. [1] A 'trait' or 'disorder' determined by a gene on the X chromosome demonstrates X-linked inheritance. In 1961, Mary Lyon proposed that in the cells of mammalian females, one X chromosome out of the two would undergo random inactivation in early embryonic life, and therefore, both males and females have a single active X. Lyon's hypothesis provided an improved understanding of the basic mechanisms responsible for X-linked diseases. [2] [3] [4] [5] Classically, the descriptions of X-linked inheritance are either X linked recessive and X linked dominant. X linked Recessive InheritanceGenerally, it manifests only in males. A male with an affected allele on his single X chromosome is hemizygous and can not transmit the disorder to their male offsprings, but all his daughters would be obligate carriers. Healthy heterozygous carrier females pass the disorder to affected sons. So from affected males, it can be transmitted to male grandchildren through carrier daughter ('diagonal' or 'Knight's move' transmission). RISK CALCULATION: The X chromosome from a male is transmitted to daughters, and the Y chromosome is transferred to sons. If an affected male has kids with a healthy female, none of his male offsprings will be affected, but all of his female offspring will be carriers. If a carrier female has kids with a healthy male, each male offspring has a 50% chance of being affected, and female offspring have a 50% chance of being a carrier.VARIABLE EXPRESSION: Heterozygous female are those who are having mutant allele on one X chromosome, and normal allele on another X. Heterozygous female may have a variable expression of X linked recessive disorder due to the random process of X inactivation involving inactivation of the X chromosome with a mutant allele in some cells while inactivation of the X chromosome with a normal allele in other cells (mosaic pattern). [1] X-LINKED DISORDERS IN FEMALES: Sometimes, females might be affected by X linked recessive disorders. This fact is explainable by one of the following possibilities.(a) Heterozygosity: X inactivation is a random phenomenon that can involve a mutant allele containing X and a normal allele X in equal proportion in the heterozygous female. It is a possibility that the active X chromosome in the majority of the cells of a heterozygous female is the one having a mutant allele (skewed X inactivation), leading to disorder expression; this has been the case in Duchenne muscular dystrophy and hemophilia A. [6] [7] (b) Homozygosity: When both X chromosomes of females have a mutant allele, as reported in hemophilia A and ichthyosis. [8] [9] (c) Translocations: If a female is having a translocation involving an autosome and one of the X chromosomes and the translocation disrupts a gene on an X chromosome, in that case, a female might be affected. This pattern has been observed in Duchenne muscular dystrophy. [10] [11] [10] (d) A female having only a single X chromosome (Turner syndrome), which is bearing a mutant allele. Hemophilia has been reported in the girl infant with the turner syndrome. [12] X linked Dominant Inheritance Male and female both are affected, but females are affected in excess and less severely. Affected males can transmit the mutant allele to female offspring but not to male offspring. Affected females can transmit the mutant allele to 50% of his male offspring and 50% of his female offspring. examples are Vitamin D resistant (hypophosphatemic) rickets, Charcot-Marie-tooth disease. [13] [14] Some X-like dominant disorders, such as incontinentia pigmenti (Bloch-Sulzberger syndrome), showed a mosaic pattern of involvement for heterozygous females. [15] X-LINKED DOMINANT LETHALS: These disorders are incompatible with early embryonic survival. They are seen only in females and not in males because, in the severe form, they will cause the death of a male embryo, but as females are less severely affected female embryo will survive. [16] Current View Many female carriers of X-linked 'recessive' disorders demonstrate abnormal phenotype. This is due to the variable expressivity of X-linked disorders and the involvement of several mechanisms (e.g. skewed X-inactivation, somatic mosaicism...etc). So, recently it has been proposed that the terms' dominant' and recessive' should be discontinued, and all disorders should categorize as X-linked. [17] [18] [19] Common X-linked Disorders Red-green color blindness is a common trait that affects at least 10% of men and only one percent of women. The red-green color blindness may be partial or complete, but the latter is much less common. Hemophilia A results from a mutation in the factor VIII gene. Hemophilia A may be inherited or may occur due to a spontaneous mutation. Acquired hemophilia A can occur if a patient develops antibodies to factor VIII. The primary cause of morbidity and mortality in hemophilia A is hemorrhage, which can range from mild to severe. Although rare, transfusions of blood can sometimes lead to transmission of HIV and hepatitis C; this was more common in the 1980s and 1990s. Duchene muscular dystrophy is associated with a mutation in the dystrophin gene and is characterized by profound muscle weakness, leading to respiratory failure and death. X-linked agammaglobulinemia results in the inability to make plasma cells and antibodies. The individual develops susceptibility to a wide range of infections, which can be fatal. Alport syndrome is an X-linked disorder that has a heterogeneous presentation. The pathology involves the basement membrane, and chiefly affects the basement membrane of the kidney in addition to the eyes and cochlea. There appears to a mutation in the type IV collagen gene. Charcot-Marie-Tooth disease is the most common inherited neurologic disorder that is characterized by an inherited neuropathy in the absence of any metabolic or biochemical dysfunction. The disorder has variable penetrance, and there are also reports of spontaneous mutations. The age of presentation does vary, but the onset of the disorder is usually within the first two decades of life. Fabry disease is an X-linked disorder that involves the lysosomes. In this disorder, there is an excessive accumulation of neutral glycosphingolipids in the vascular endothelium, smooth muscle, and epithelial cells. The continued accumulation of glycosphingolipids accounts for dysfunction in almost every organ in the body. In a young person who presents with a history of skin lesions, renal failure, stroke, or a heart attack, one must think about Fabry disease. Other less common X-linked disorders include adrenoleukodystrophy, Kabuki syndrome, and Lesch-Nyhan syndrome.

HSD10 disease in a female: A case report and review of literature.

Abstract: HSD10 disease is a rare X-linked mitochondrial disorder caused by pathogenic variants in the HSD17B10 gene. The phenotype results from impaired 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10) protein structure and function. HSD10 is a multifunctional protein involved in enzymatic degradation of isoleucine and branched-chain fatty acids, the metabolism of sex hormones and neurosteroids, as well as in regulating mitochondrial RNA maturation. HSD10 disease is characterised by progressive neurologic impairment. Disease onset is varied and includes neonatal-onset, infantile-onset and late-onset in males. Females can also be affected. Our index case is a 45-month-old female, who initially presented at 11 months of age with global developmental delay. She subsequently began to lose previously acquired cognitive and motor skills starting around 29 months of age. Brain MRI showed abnormalities in the basal ganglia indicative of possible mitochondrial disease. Urine organic acid analysis revealed elevations of 2-methyl-3-hydroxybutyric acid and tiglyglycine. HSD17B10 gene sequencing revealed a likely pathogenic variant, NM_001037811.2:c.439C>T (p.Arg147Cys) inherited from her mother, expected to be causative of HSD10 disease. Her X-chromosome inactivation study is consistent with a skewed X-inactivation pattern. We report a female patient with HSD10 disease caused by a missense pathogenic variant, Arg147Cys in the HSD17B10 gene. The patient is the fifth severely affected female with this disease. This case adds to the small number of known affected families with this highly variable disease in the literature. These findings support the possibility of X-inactivation patterns influencing the penetrance of HSD10 disease in females.

Case Report: Wiskott-Aldrich Syndrome Caused by Extremely Skewed X-Chromosome Inactivation in a Chinese Girl

Abstract: Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of Wiskott-Aldrich syndrome protein due to WAS gene mutation, which is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high risk of autoimmune complications and hematological malignancies. Although affected males with WAS usually manifest severe symptoms, female carriers have no significant clinical manifestations. Here, we describe a Chinese girl diagnosed with WAS carrying a heterozygous missense mutation in exon 2 of the WAS gene. The patient presented with persistent thrombocytopenia with small platelets and decreased WAS protein detected by flow cytometry and western blot analysis. The methylation analysis of the HUMARA gene displayed an extremely skewed X-chromosome inactivation (SXCI) pattern, where the X-chromosomes bearing normal WAS gene were predominantly inactivated, leaving the mutant gene active. Hence, our results suggest that completely inactivating the unaffected paternal X-chromosomes may be the reason for such phenotype in this female patient. SXCI has important implications for genetic counseling of female carriers with a family history of WAS.

Hemophilia A and C in a female: The first case report in literature.

Abstract: Introduction One of the relatively rare hemostatic disorders is coagulation factors' deficiency, where a single factor or multiple factors can be deficient. All hereditary coagulation factors' deficiencies are autosomal recessive, so they can manifest in both genders, but Hemophilia A and B are X-linked disorders. Therefore, females can rarely be affected. This paper reports the first case of simultaneous coagulation factors’ deficiencies of FVIII and FXI in a female. Case presentation A 17-year-old female came to the office due to prolonged epistaxis, with a history of severe menstrual bleeding and frequent episodes of epistaxis. In her familial history, a brother complained of epistaxis episodes. Bleeding time and prothrombin time were normal but activated partial thromboplastin time was increased. Von Willebrand disease was excluded, and she was diagnosed with hemophilia A and C. Discussion Females can be affected with X-linked disorders such as hemophilia A and B in some rare cases: a carrier mother and affected father, skewed X chromosome inactivation, Turner syndrome, inhibiting antibodies (acquired hemophilia), or a sporadic mutation on the most activated X chromosome. On the other hand, Hemophilia C is an autosomal recessive disease. Treatment of such cases is a challenge, and the recombinant coagulation factors are the treat-of-choice. Conclusion Although Von Willebrand disease is the most common hereditary bleeding disorder in females, other rare diseases could be suspected such as Hemophilia. X-linked Hemophilia should be kept in mind as a differential diagnosis in any female patient suffering from hemorrhage.

A female carrier of a novel DMD mutation with slightly skewed X-chromosome inactivation shows a suspected case of Becker muscular dystrophy in a Chinese family.

Abstract: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are both caused by mutations in DMD gene effecting the expression of dystrophin. Generally female carriers are asymptomatic; however, it has been suggested that carriers may exhibit symptoms. We investigated a 6-year-old Chinese girl exhibiting a suspected BMD phenotype, including persistently elevated creatine kinase and creatine kinase isoenzyme levels. The proband harbored a novel heterozygous mutation, c.3458_3459insAA, within exon 26 of the DMD gene inherited from her mother who had a completely normal phenotype and presented with mosaicism in her lymphocytes with 45, X [17%]/46, XX [83%]. In addition, X-chromosome inactivation (XCI) patterns in the peripheral blood of the child were slightly skewed: proband with 62% (mutant allele)/38% (normal allele) when compared with her mother with 32/68%. Amplification of regions of the cDNA revealed different ratios for the expression of these alleles: proband with 50/50% and her mother with 20/80%. Real-time PCR showed that mRNA expression was significantly decreased in both. We proposed that a frameshift or nonsense mutation may contribute to the development of symptoms in carriers. These phenotypes correlate with nonrandom XCI patterns and are compounded by the locus of the mutation. For incompletely skewed XCI patterns, although the mutant allele could suppress the expression of a normal allele, carriers would remain asymptomatic as long as there was adequate compensation from the normal allele. We also proposed a mechanism where mRNA from the mutant allele may be unstable and easily degraded, allowing for phenotypic compensation by the wildtype allele.

Molecular and Cellular Basis of Hyper-Assembly, Protein Aggregation and Impaired Neurodevelopment Driven by a Rare Pathogenic Mutation in DDX3X

Abstract: Current studies estimate that 1-3% of females with unexplained Intellectual Disability (ID) present de novo splice site, nonsense, frameshift, or missense mutations in the DDX3X protein (DEAD-Box Helicase 3 X-Linked). However, the cellular and molecular mechanisms by which DDX3X mutations impair brain development are not fully comprehended. Here, we show that the ID-linked missense mutation L556S renders DDX3X prone to aggregation. By using a combination of biophysical assays, in vitro and in vivo imaging approaches, we demonstrate that this mutant assemble solid-like condensates and amyloid-like fibrils. Although we observed greatly reduced expression of the mutant allele in the patient who exhibits skewed X inactivation, this appears to be enough to sequestrate healthy protein into solid-like ectopic granules, compromising cell function. Reduced viability of SH-SY5Y cells and impaired development of patient-derived brain organoids unfold with aberrant granules formation. Therefore, our data suggests ID-linked DDX3X L556S mutation as a disorder arising from protein misfolding and aggregation.