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Role of Epigenetics in Immunity and Immune Response to Vaccination
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
ncRNAs longer than 200 nt are classified as long ncRNAs. In a fashion similar to pre-miRNAs lncRNAs are also transcribed by RNA polymerase II and undergo 5′ capping and polyadenylation. The human genome encodes for approximately 16,000 lcnRNAs which give rise to almost 30,000 different transcripts. Despite being considered new additions to the field of RNA biology, the function of some lncRNAs has been known for almost 30 years. One of the lncRNAs whose function has been identified in the early 1990s is lncRNA Xist. Xist plays a central role in X-chromosome inactivation (Brown et al. 1992). Recent studies have demonstrated several new functions for lncRNAs including antiviral response in addition to regulation of development and differentiation (Fatica and Bozzoni 2014; Fortes and Morris 2016). A common mechanism for exerting such functions for lncRNAs is to act as post transcriptional regulators by altering mRNA/protein stability and translation (Yoon, Abdelmohsen, and Gorospe 2013).
Genetic counselling in Mendelian disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
There is a considerable amount of direct evidence for X-chromosome inactivation in human diseases, which may be expressed in several ways. Some disorders show ‘mosaic’ or ‘patchy’ changes in heterozygotes; thus, patchy retinal changes are seen in carriers for X-linked retinitis pigmentosa and choroideraemia, and patchy muscle biopsy changes may be found in carriers for Duchenne muscular dystrophy. More commonly, variability in X inactivation can result in a milder and more variable expression of clinical and biochemical changes. Thus, in X-linked hypophosphataemic rickets, generally considered to be an X-linked dominant condition, affected females can have milder disease than their affected male relatives; conversely, in haemophilia A, usually classed as an X-linked recessive condition, some carriers show a mild bleeding tendency in addition to reduced levels of factor VIII. The implications for tests of carrier detection in X-linked diseases are discussed in Chapter 7.
Clinical Cytogenetics and Testing for Developmental Disabilities
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Joan H. M. Knoll, Linda D. Cooley
X chromosome inactivation refers to the process whereby many genes on one X chromosome are inactivated to equalize the X-linked gene expression in males and females. As a general rule, there is only one active X per cell regardless of the number of X chromosomes and in the case of X/autosome translocations, the normal X is generally inactivated to prevent spread of inactivation into autosomal genes. The inactive X can be detected by its late replication and dense compaction (42,43). A more comprehensive description of X inactivation is presented elsewhere in this textbook.
Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature
Published in Expert Review of Clinical Immunology, 2022
Charmaine van Eeden, Mohammed S. Osman, Jan Willem Cohen Tervaert
The most distinct genetic feature related to the development of ME/CFS, is the profound gender bias toward females, who are four times more likely to develop ME/CFS than their male counterparts [103,104]. Numerous genes involved in immune and mitochondrial function are located on the X chromosome, when more than one copy is present, as is typical in women; one copy is usually deactivated [105]. Studies looking at X chromosome inactivation have, however, shown that up to 23% of X-linked genes escape deactivation, leading to over activation. One such gene is TLR7, a single-stranded RNA (ssRNA) sensor, essential to innate and B cell defense from RNA viruses [106]. Over activation of TLR7 can lead to activity against endogenous ssRNA, leading to autoimmunity, and has recently been implicated in increased risk of developing SLE [106].
Emerging gene therapy products for RPGR-associated X-linked retinitis pigmentosa
Published in Expert Opinion on Emerging Drugs, 2022
Cristina Martinez-Fernandez de la Camara, Jasmina Cehajic-Kapetanovic, Robert E. MacLaren
For RPGR-related RP, as for other recessive disorders, the potential benefits of gene replacement therapy are indisputable. The delivery of a functioning copy of RPGR to supplement the mutant gene in surviving photoreceptors would provide these cells with normal RPGR protein and restore function. A potential regeneration mechanism by which the outer segments of the degenerated photoreceptors are rehabilitated after gene therapy has also been suggested [30,31]. Being an X-linked disease, one could assume that only hemizygous males are affected whilst heterozygous females can only carry the mutation and present a mild, subclinical phenotype. However, differences in the X chromosome inactivation ratio result in a phenotypic variability in female carriers. In cases where the normal X chromosome is inactivated, randomly or because some mutations may skew the inactivation process and select the mutant allele, females can present a severe male-pattern phenotype, with clinically significant visual impairment [32–34]. These severely affected females could also benefit from the gene replacement therapy.
X marks the spot in autoimmunity
Published in Expert Review of Clinical Immunology, 2022
Alessio Gerussi, Chiara Caime, Eleonora Binatti, Claudio Cappadona, Laura Cristoferi, Rosanna Asselta, M. Eric Gershwin, Pietro Invernizzi
Females (XX) and males (XY) are naturally imbalanced in terms of sex chromosomes, since women carry two X chromosomes. X-Chromosome Inactivation (XCI) occurs for dosage compensation: females silence the transcription of one of the two X chromosomes via a complex epigenetic program. Pseudo-autosomal regions (PAR) have homologues on the Y chromosome and do not undergo XCI. XCI starts in the early embryo when the long non-coding RNA XIST (X–inactive specific transcript) is upregulated on one X. Later, XIST recruits heterochromatic marks and produces several conformational changes that ultimately lead to an inactive X (Xi) (Figure 1) [43]. In placental mammals, XCI occurs at random in the embryo, meaning that females are mosaics because they have either the paternal or the maternal active X chromosome[44]. Whereas marsupials, where the Xi is inherited, random XCI needs a system that counts the number of active X: this mechanism has yet to be identified[45].