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Aicardi Syndrome and Klinefelter Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Gene dosage compensation involves genetic equalization through X-inactivation, which randomly silences one of the X-chromosomes in female cell and keeps the other X-chromosome transcriptionally active. In cases of X-chromosome aneuploidy, extra X-chromosome is similarly inactivated. However, two pseudoautosomal regions (PAR1 and PAR2) along with up to 15% of additional genes on the short arm of the X chromosome (Xp) escape inactivation and are expressed from both X-chromosomes. In males with Klinefelter syndrome, extra copies of these escapee genes are transcriptionally active, and their overexpressions modulate the related cellular and developmental pathways. Located at the terminal region of the short arms and consisting of 24 genes (including short-stature homeobox-containing gene on chromosome X or SHOX), PAR1 is required during male meiosis for X–Y chromosome pairing, a process which is known to have a critical function in spermatogenesis. PAR2 is situated at the tips of the long arms and contains four genes (Eif2s3x, Ddx3x, Kdm5c, Kdm6a).
Discovery and research
Published in Peter S. Harper, The Evolution of Medical Genetics, 2019
Goodfellow's work on the molecular structure of the Y chromosome and its role in sex determination was carried out at the Imperial Cancer Research Fund laboratories in London, which were at this time directed by Walter Bodmer, with whom Goodfellow had previously worked in Oxford. His group collaborated closely with that of Robin Lovell-Badge, at National Institute of Medical Research, Mill Hill, who was analysing sexual development in transgenic mice. The Y chromosome had always been something of a ‘poor relation’ of the X chromosome, and little was known of its gene structure or function except that there was a region of homology between X and Y involved in chromosome pairing at meiosis, the pseudoautosomal region, while information was also given by which parts were missing in rare patients with abnormalities involving the Y chromosome.
Genetic counselling in Mendelian disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The pseudoautosomal region of Xp has homology with part of the Y chromosome and is involved in pairing between the sex chromosomes at meiosis. The process of X inactivation is itself controlled by a different region of the X chromosome, the X-inactivation centre including the Xist locus on the proximal long arm. The Xist transcript does not encode a protein but functions as a large, non-coding RNA molecule.
A 7-year old female with arthrogryposis multiplex congenita, Duane retraction syndrome, and Marcus Gunn phenomenon due to a ZC4H2 gene mutation: a clinical presentation of the Wieacker-Wolff syndrome
Published in Ophthalmic Genetics, 2021
Deena Godfrey, Alcy Torres, Gena Heidary, Hovra Zahoor, Arthur Lee, Gerard Berry, Elizabeth Engle
The proband had a normal female karyotype (46, XX) and, by microarray, a 723 kb gain in the Xp22.33 pseudoautosomal region of unknown significance. The Distal Arthrogryposis Panel (University of Chicago) reported a paternally inherited variant of FBN2 of unknown significance. Clinical whole exome trio sequencing (≥20x coverage, >98% of bases covered, Ambry Diagnostics) followed by standard filtering assuming autosomal and X-linked dominant and recessive modes of inheritance revealed a de novo heterozygous c.199 C > T ZC4H2 variant (NM_018684) predicted to introduce a premature stop codon in exon 2 (p.R67*), with a CADD pathogenicity prediction score of 37 (10). The variant was absent from the gnomAD database and was previously reported in a child with AMC, facial asymmetry, cleft palate, severe developmental delay and growth retardation; there was no mention of Duane syndrome or strabismus (Frints eet al. family 17) (7). Based on the clinical overlap of the patient’s reported signs and symptoms and existing evidence, this alteration was classified as pathogenic (7).
Mediterranean Y-chromosome 2.0—why the Y in the Mediterranean is still relevant in the postgenomic era
Published in Annals of Human Biology, 2018
Maarten H. D. Larmuseau, Claudio Ottoni
The human Y-chromosome differs markedly from the other chromosomes in inheritance, size, genomic structure, content and evolutionary trajectory (Jobling et al., 2013). It is the sex-determining chromosome, which is essential for male sexual differentiation and spermatogenesis, and evidence for its role in human biology beyond male reproduction is growing (Massaia & Xue, 2017). Between the two pseudoautosomal regions (PAR) of XY sequence homology at the tips of the arms, which are required for proper chromosome segregation during meiosis (Mensah et al., 2014), the male-specific region of the Y-chromosome (MSY) is passed down from father to son and escapes the reshuffling effects of crossing-over. This MSY region, also known as the non-recombining region of the Y-chromosome (NRY), has a strong structural complexity with many repeated elements and segmental duplications, which covers ∼35% of its length, and only contains ∼78 protein-coding genes (Jobling & Tyler-Smith, 2017; Skaletsky et al., 2003).
Is chronic pain as an autoimmune disease?
Published in Canadian Journal of Pain, 2022
One of the two X chromosomes has been observed to randomly undergo permanent somatic cell X-inactivation during embryogenesis. The purpose of this process is suggestive that females resemble males in maintaining only one functional copy of the X chromosome per somatic cell. X chromosome silencing occurs via two potential mechanisms, namely (1) epigenetic changes that include chromatin modification39 and (2) the coating of one X chromosome by the X‐inactive specific transcript (XIST).40–42 The second mechanism requires the Ying Yang 1 protein, which activates XIST43 and attaches it to the X chromosome.44 It is noteworthy that 10% to 15% of genes that are localized on the X chromosome escape X-inactivation. This results in their biallelic expression and skewed transcript levels in females.45 X-inactivation silencing occurs primarily to genes within the pseudoautosomal region at the end of the short arm of the X chromosome, denoting nonrecombining sequences. A large number of these genes are associated with a pathological state such as major psychiatric disorder, systemic lupus erythematosus, Rett syndrome, and thyroid autoimmunity.46–48 Many sexually dimorphic variances in disease susceptibility could potentially be attributed to altered gene expression that is associated with an escape from X chromosome inactivation. To support this concept, sex chromosome has been linked to abnormalities of brain disorders,49 such as X chromosome inactivation and its association with neural development, disease,50 and murine Ying Yang 1 expression, which plays a role in both morphine analgesia and inflammatory pain.51