Browsing by Subject "X chromosome inactivation"

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Open Access
Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases
(BioMed Central, 2009) Chabchoub, G.; Uz, E.; Maalej, A.; Mustafa, C. A.; Rebai, A.; Mnif, M.; Bahloul, Z.; Farid, N. R.; Ozcelik, T.; Ayadi, H.
Introduction The majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases.
Open Access
Disruption of HDX gene in premature ovarian failure
(Taylor & Francis, 2013) Okten, G.; Gunes, S.; Onat, O. E.; Tukun, A.; Ozcelik, T.; Kocak, I.
We present a case of a 19-year-old phenotypically normal girl with premature ovarian failure. Cytogenetic analysis using G banding and fluorescence in situ hybridization (FISH) from cultured peripheral blood lymphocytes of the patient and the family revealed a de novo X;15 translocation and the imbalance to be 46,X,t(X;15)(Xpter → Xq21::15q11 → 15qter;15pter → 15q11::Xq21 → Xqter). ish (CEPX+, wep15+, ISNRPN+, PML+, D15S10+, wcp15-, SNRRN-, PML-)[20]. The X chromosome inactivation (XCI) assay revealed a completely skewed XCI pattern in which selective pressure favors an active maternal allele. The Affymetrix 2.7 M cytogenetics whole-Genome array confirmed the chromosomal imbalance and identified disruption of the HDX gene at Xq21, the translocation breakpoint. © 2013 Informa Healthcare USA, Inc.
Open Access
Endothelial progenitor cells display clonal restriction in multiple myeloma
(BioMed Central Ltd., 2006) Braunstein, M.; Özçelik, T.; Baǧişlar, S.; Vakil, V.; Smith, E. L. P.; Dai, K.; Akyerli, C. B.; Batuman O. A.
Background: In multiple myeloma (MM), increased neoangiogenesis contributes to tumor growth and disease progression. Increased levels of endothelial progenitor cells (EPCs) contribute to neoangiogenesis in MM, and, importantly, covary with disease activity and response to treatment. In order to understand the mechanisms responsible for increased EPC levels and neoangiogenic function in MM, we investigated whether these cells were clonal by determining X-chromosome inactivation (XCI) patterns in female patients by a human androgen receptor assay (HUMARA). In addition, EPCs and bone marrow cells were studied for the presence of clonotypic immunoglobulin heavy-chain (IGH) gene rearrangement, which indicates clonality in B cells; thus, its presence in EPCs would indicate a close genetic link between tumor cells in MM and endothelial cells that provide tumor neovascularization. Methods: A total of twenty-three consecutive patients who had not received chemotherapy were studied. Screening in 18 patients found that 11 displayed allelic AR in peripheral blood mononuclear cells, and these patients were further studied for XCI patterns in EPCs and hair root cells by HUMARA. In 2 patients whose EPCs were clonal by HUMARA, and in an additional 5 new patients, EPCs were studied for IGH gene rearrangement using PCR with family-specific primers for IGH variable genes (VH). Results: In 11 patients, analysis of EPCs by HUMARA revealed significant skewing (≥ 77% expression of a single allele) in 64% (n = 7). In 4 of these patients, XCI skewing was extreme (≥ 90% expression of a single allele). In contrast, XCI in hair root cells was random. Furthermore, PCR amplification with VH primers resulted in amplification of the same product in EPCs and bone marrow cells in 71 % (n = 5) of 7 patients, while no IGH rearrangement was found in EPCs from healthy controls. In addition, in patients with XCI skewing in EPCs, advanced age was associated with poorer clinical status, unlike patients whose EPCs had random XCI. Conclusion: Our results suggest that EPCs in at least a substantial subpopulation of MM patients are related to the neoplastic clone and that this is an important mechanism for upregulation of tumor neovascularization in MM. © 2006 Braunstein et al; licensee BioMed Central Ltd.
Open Access
Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity
(Nature Publishing Group, 2006) Ozcelik, T.; Uz, E.; Akyerli, C. B.; Bagislar, S.; Mustafa, C. A.; Gursoy, A.; Akarsu, N.; Toruner, G.; Kamel, N.; Gullu, S.
The etiologic factors in the development of autoimmune thyroid diseases (AITDs) are not fully understood. We investigated the role of skewed X-chromosome inactivation (XCI) mosaicism in female predisposition to AITDs. One hundred and ten female AITDs patients (81 Hashimoto's thyroiditis (HT), 29 Graves' disease (GD)), and 160 female controls were analyzed for the androgen receptor locus by the HpaII/polymerase chain reaction assay to assess XCI patterns in DNA extracted from peripheral blood cells. In addition, thyroid biopsy, buccal mucosa, and hair follicle specimens were obtained from five patients whose blood revealed an extremely skewed pattern of XCI, and the analysis was repeated. Skewed XCI was observed in DNA from peripheral blood cells in 28 of 83 informative patients (34%) as compared with 10 of 124 informative controls (8% P<0.0001). Extreme skewing was present in 16 patients (19%), but only in three controls (2.4% P<60;0.0001). The buccal mucosa, and although less marked, the thyroid specimens also showed skewing. Analysis of two familial cases showed that only the affected individuals demonstrate skewed XCI patterns. Based on these results, skewed XCI mosaicism may play a significant role in the pathogenesis of AITDs.
Open Access
Extreme clonality in lymphoblastoid cell lines with implications for allele specific expression analyses
(2008) Plagnol V.; Uz, E.; Wallace, C.; Stevens H.; Clayton, D.; Ozcelik, T.; Todd J.A.
Lymphoblastoid cell lines (LCL) are being actively and extensively used to examine the expression of specific genes and (genome-wide expression profiles, including allele specific expression assays. However, it has recently been shown that approximately 10% of human genes exhibit random patterns of monoallelic expression within single clones of LCLs. Consequently allelic imbalance studies could be significantly compromised if bulk populations of donor cells are clonal, or near clonal. Here, using X chromosome inactivation as a readout, we confirm and quantify widespread near monoclonality in two independent sets of cell lines. Consequently, we recommend where possible the use of bulk, non cell line, ex vivo cells for allele specific expression assays. © 2008 Plagnol et al.
Open Access
Extremely skewed X-chromosome inactivation patterns in women with recurrent spontaneous abortion
(Wiley-Blackwell Publishing Asia, 2006) Bagislar, S.; Ustuner, I.; Cengiz, B.; Soylemez, F.; Akyerli, C. B.; Ceylaner, S.; Ceylaner, G.; Acar, A.; Ozcelik, T.
Background: The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of recurrent spontaneous abortion (RSA) but the results obtained were conflicting. Aims: We therefore investigated the XCI patterns in peripheral blood DNA obtained from 80 patients who had RSA and 160 age-matched controls. Methods: Pregnancy history, age, karyotype, and disease information was collected from all subjects. The methylation status of a highly polymorphic cytosine-adenine-guanine repeat in the androgen-receptor (AR) gene was determined by use of methylation-sensitive restriction enzyme HpaII and polymerase chain reaction. Results: Skewed XCI (> 8 5% skewing) was observed in 13 of the 62 patients informative for the AR polymorphism (20.9%), and eight of the 124 informative controls (6.4%) (P = 0.0069; χ 2 test). More importantly, extremely skewed XCI, defined as > 90% inactivation of one allele, was present in 11 (17.7%) patients, and in only two controls (P = 0.0002; χ 2 test). Conclusions: These results support the interpretation that disturbances in XCI mosaicism may be involved in the pathogenesis of RSA.
Open Access
Increased frequency of extremely skewed X chromosome inactivation in juvenile idiopathic arthritis
(John Wiley & Sons, Inc., 2009) Uz, E.; Mustafa, C.; Topaloglu, R.; Bilginer, Y.; Dursun, A.; Kasapcopur, O.; Ozen, S.; Bakkaloglu, A.; Ozcelik, T.
Objective. Juvenile idiopathic arthritis (JIA) is a childhood rheumatic disease of unknown etiology. Two subgroups of JIA, i.e., oligoarticular and polyarticular, are thought to have an autoimmune component, and show a higher female:male ratio. Skewed X chromosome inactivation (XCI) has previously been shown to be associated with scleroderma and autoimmune thyroiditis, 2 autoimmune disorders occurring predominantly in females. This study was undertaken to extend the analysis to the pediatric age group and to determine the XCI profiles of patients with JIA.
Open Access
Multiscale analysis of SRY‐positive 46,XX testicular disorder of sex development: Presentation of nine cases
(Wiley, 2020-06-04) Akar, Ö. S.; Güneş, S.; Abur, U.; Altundağ, E.; Aşçı, R.; Onat, Onur Emre; Özçelik, Tayfun; Oğur, G.
46,XX testicular disorder of sex development (46,XX TDSD) is a relatively rare condition characterised by the presence of testicular tissue with 46,XX karyotype. The present study aims to reveal the phenotype to genotype correlation in a series of sex‐determining region Y (SRY)‐positive 46,XX TDSD cases. We present the clinical findings, hormone profiles and genetic test results of six patients with SRY‐positive 46,XX TDSD and give the details and follow‐up findings of our three of previously published patients. All patients presented common characteristics such as azoospermia, hypergonadotropic hypogonadism and an SRY gene translocated on the terminal part of the short arm of one of the X chromosomes. Mean ± standard deviation (SD) height of the patients was 164.78 ± 8.0 cm. Five patients had decreased secondary sexual characteristics, and three patients had gynaecomastia with varying degrees. Five of the seven patients revealed a translocation between protein kinase X (PRKX) and inverted protein kinase Y (PRKY) genes, and the remaining two patients showed a translocation between the pseudoautosomal region 1 (PAR1) of X chromosome and the differential region of Y chromosome. X chromosome inactivation (XCI) analysis results demonstrated random and skewed XCI in 5 cases and 1 case, respectively. In brief, we delineate the phenotypic spectrum of patients with SRY‐positive 46,XX TDSD and the underlying mechanisms of Xp;Yp translocations.
Open Access
De novo balanced (X;14) translocation in a patient with recurrent miscarriages: Case report
(2011) Alpaslan Pinarli F.; Ökten G.; ÖzçelIk, T.; Kara, N.; Güneş, S.; Koçak I.
We report a 23-year-old phenotypically normal female patient who had previously suffered from recurrent spontaneous abortion (RSA) who found to have an X;14 trans location and a Methylene- Tetrahdrofolate-Reductase (MTHFR) C677T heterozygote mutation. G-banding cytogenetic analysis was cultured from the peripheral blood lymphocy tes. MTHFR, factor V Leiden and prothrombin gene mutations were studied from DNA obtained from peripheral blood lym- phocytes with stripassay. DNA for X inactivation pattern study was also obtained with the method described above. G-banding cytogentic analysis from cultured peripheral blood lymphocytes of the patient revealed 46,XderX,t(X;14)(q13;q32) and found to be heterozygous for C677T MTHFR mutation. An X inactivation pattern study revealed a complete inactivated nor mal X chromosome, asexpected. The possible causes of recurrent miscarriages in our patient were unbalanced gametes, skewed X inactivation and MTHFR C677T heterozygote mutation. © 2011 by Türkiye Klinikleri.
Open Access
Skewed X chromosome inactivation in blood cells of women with scleroderma
(John Wiley & Sons, Inc., 2005) Özbalkan, Z.; Baǧişlar, S.; Kiraz, S.; Akyerli, C. B.; Özer H. T. E.; Yavuz, Ş.; Birlik, A. M.; Çalgüneri, M.; Özçelik, T.
Objective. Scleroderma (SSc) is an autoimmune disease of unknown etiology. The disease is 3-8 times more frequent in women than in men. The role of X chromosome inactivation (XCI) in the predisposition of women to autoimmunity has been questioned. Until now this has not been illustrated experimentally. This study was undertaken to test the hypothesis that disturbances in XCI mosaicism may be involved in the pathogenesis of the disease in female patients with SSc. Methods. Seventy female SSc patients and 160 female controls were analyzed for the androgen receptor locus by the Hpa II/polymerase chain reaction assay to assess XCI patterns in DNA extracted from peripheral blood cells. Furthermore, skin biopsy samples were obtained from 5 patients whose blood revealed an extremely skewed pattern of XCI, and the analysis repeated. Since microchimerism in SSc was reported, Y chromosome sequences were investigated in all samples. Results. Skewed XCI was observed in DNA from peripheral blood cells in 35 of 55 informative patients (64%), as compared with 10 of 124 informative controls (8%) (P < 0.0001). Extreme skewing was present in 27 of the patient group (49%), as compared with only 3 of the controls (2.4%) (P < 0.0001). However, XCI was random in all skin biopsy samples. The potential contribution of microchimerism to the random XCI pattern is highly unlikely based on the medical histories of the patients. Conclusion. Skewed XCI mosaicism may play a significant role in the pathogenesis of SSc.
Open Access
Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene
(BMJ Group, 2008) Kaplan, Y.; Vargel, I.; Kansu, T.; Akin, B.; Rohmann, E.; Kamaci, S.; Uz, E.; Ozcelik, T.; Wollnik, B.; Akarsu, N. A.
Aims: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. Methods: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. Results: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. Conclusions: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.
Open Access
Skewed X-chromosome inactivation in scleroderma
(Springer New York, 2008) Uz, E.; Loubiere, L. S.; Gadi, V. K.; Ozbalkan, Z.; Stewart, J.; Nelson, J. L.; Ozcelik, T.
Scleroderma is a female-prevalent autoimmune disease of unclear etiology. Two fundamental gender differences, skewed X-chromosome inactivation (XCI) and pregnancy-related microchimerism, have been implicated in scleroderma. We investigated the XCI patterns of female scleroderma patients and the parental origin of the inactive X chromosome in those patients having skewed XCI patterns (>80%). In addition, we investigated whether a correlation exists between XCI patterns and microchimerism in a well-characterized cohort. About 195 female scleroderma patients and 160 female controls were analyzed for the androgen receptor locus to assess XCI patterns in the DNA extracted from peripheral blood cells. Skewed XCI was observed in 67 (44.9%) of 149 informative patients and in 10 of 124 healthy controls (8.0%) [odds ratio (OR) = 9.3 (95% confidence interval (CI) 4.3-20.6, P < 0.0001)]. Extremely skewed XCI (>90%) was present in 44 of 149 patients (29.5%) but only in 3 of 124 controls (2.4%; OR = 16.9; 95% CI 4.8-70.4, P < 0.0001). Parental origin of the inactive X chromosome was investigated for ten patients for whom maternal DNA was informative, and the inactive X chromosome was of maternal origin in eight patients and of paternal origin in two patients. Skewed XCI mosaicism could be considered as an important risk factor in scleroderma.
Open Access
X chromosome inactivation and female predisposition to autoimmunity
(Springer New York, 2008) Ozcelik, T.
[No abstract available]