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  • 1
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    An RNA-informed dosage sensitivity map reflects the intrinsic functional nature of genes
    Elsevier BV ; 2023
    In:  The American Journal of Human Genetics Vol. 110, No. 9 ( 2023-09), p. 1509-1521
    Details
    In: The American Journal of Human Genetics, Elsevier BV, Vol. 110, No. 9 ( 2023-09), p. 1509-1521
    Type of Medium: Online Resource
    ISSN: 0002-9297
    URL: Article
    DOI: 10.1016/j.ajhg.2023.08.002
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 1473813-2
    SSG: 12
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  • 2
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    AB0016 ASSOCIATION OF PTPN22 GENETIC VARIANTS WITH DISEASE SUSCEPTIBILITY AND CLINICAL VARIABLES IN PRIMARY SJÖGREN SYNDROME
    BMJ ; 2020
    In:  Annals of the Rheumatic Diseases Vol. 79, No. Suppl 1 ( 2020-06), p. 1311.1-1312
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 1311.1-1312
    Abstract: Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by dysfunction of exocrine glands secondary to lymphocytic infiltration. Lymphoid tyrosine phosphatase (LYP) regulates T and B lymphocyte activation. PTPN22 gene encodes LYP; multiple polymorphic variants have been described as genetic risk factor of autoimmune diseases. Objectives: The aim was to analyze the PTPN22 rs2488457G 〉 C, rs33996649G 〉 A, and rs2476601C 〉 T genetic variants relationship with the development risk of pSS in the western Mexico population. Methods: One hundred and eighty healthy subjects (HS) and 150 pSS patients, classified according to EULAR 2016 criteria, were included. The genetic variants and mRNA expression were determined through PCR-RFLP and qPCR assays. Results: The frequency of heterozygote rs33996649GA genotype was higher in pSS patients than HS [OR=3.143 (1–10.234), p=0.046], and also, rs33996649GA genotype was associated with high SSDAI score (p=0.01). The pSS patients showed 44-fold more mRNA expression in comparison with HS (p=0.002), and mRNA expression correlates with SSDAI (r 2 =0.512, p=0.006). Conclusion: The rs33996649G 〉 A genetic variant of the PTPN22 gene is associated with increased development risk of pSS in the western Mexican population. The expression mRNA correlates with disease activity in pSS. References: [1]Brito-Zerón, P., Baldini, C., Bootsma, H., Bowman, S. J., Jonsson, R., Mariette, X., Ramos-Casals, M. (2016). Sjögren syndrome. Nature Reviews Disease Primers , 2(July), 1–20. https://doi.org/10.1038/nrdp.2016.47 [2]Stanford, S. M., & Bottini, N. (2014). PTPN22: The archetypal non-HLA autoimmunity gene. Nature Reviews Rheumatology , 10 (10), 602–611.https://doi.org/10.1038/nrrheum.2014.109 [3]Chen, Z., Zhang, H., Xia, B., Wang, P., Jiang, T., Song, M., & Wu, J. (2013). Association of PTPN22 gene (rs2488457) polymorphism with ulcerative colitis and high levels of PTPN22 mRNA in ulcerative colitis. International Journal of Colorectal Disease , 28 (10), 1351–1358. https://doi.org/10.1007/s00384-013-1671-3 [4]Machado-Contreras, J. R., Muñoz-Valle, J. F., Cruz, A., Salazar-Camarena, D. C., Marín- Rosales, M., & Palafox-Sánchez, C. A. (2016b). Distribution of PTPN22 polymorphismsin SLE from western Mexico: correlation with mRNA expression and disease activity. Clinical and Experimental Medicine , 16 (3), 399–406. https://doi.org/10.1007/s10238-015-0359-0 Disclosure of Interests: None declared
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2020-eular.2173
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1481557-6
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  • 3
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    Trends in prenatal diagnosis: An analysis of 40 years of Medical Subject Heading ( MeSH ) terms in publications
    Wiley ; 2020
    In:  Prenatal Diagnosis Vol. 40, No. 13 ( 2020-12), p. 1636-1640
    Details
    In: Prenatal Diagnosis, Wiley, Vol. 40, No. 13 ( 2020-12), p. 1636-1640
    Abstract: To understand the evolution of the field of prenatal diagnosis over the past four decades. Method We analyzed the publications in the journal Prenatal Diagnosis from its inception in 1980 to 2019 using Medical Subject Headings (MeSH) to examine the major research topics and trends. The results were analyzed by 10‐year intervals. Results Publications on prenatal cytogenetics, congenital anomalies and fetal imaging predominated during the first three decades, with a steady increase in molecular genetics over time. Publications on NIPT did not appear until the most recent decade and are likely under‐counted because there was no MeSH term for NIPT until 2020. Conclusion The topics covered in Prenatal Diagnosis articles have evolved considerably over the past four decades and reflect a response to advances in technology and widespread incorporation of prenatal screening and diagnosis into standard obstetric care. The strengths of this analysis are its objective nature, its use of the standard MeSH terms used for coding, and application of a novel cluster analysis to visualize trends. The analysis also pointed out the fact that MeSH terms in this sub‐specialty area are often inconsistent due to manually coding based on individual subject matter expertise.
    Type of Medium: Online Resource
    ISSN: 0197-3851 , 1097-0223
    URL: Issue
    URL: Article
    DOI: 10.1002/pd.v40.13
    DOI: 10.1002/pd.5871
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1491217-X
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  • 4
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    OP0325 EFFECT OF CITRULLINATION ON THE PROCESSING AND PRESENTATION OF RHEUMATOID ARTHRITIS AUTOANTIGENS
    BMJ ; 2020
    In:  Annals of the Rheumatic Diseases Vol. 79, No. Suppl 1 ( 2020-06), p. 200.1-200
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 200.1-200
    Abstract: Citrullinated proteins are hallmark targets of the autoimmune response in rheumatoid arthritis (RA), 1 but the mechanism by which immune tolerance is broken to these self-proteins is poorly understood. CD4 + T cells are implicated as important drivers of the autoimmune response due to the high-affinity, class-switched nature of anti-citrullinated protein antibodies (ACPAs) present in the majority of RA patients and the prominent genetic contribution of certain HLA-DR alleles to RA susceptibility. 2,3 However, the precise effect of citrullination on MHC class II antigen processing and presentation of autoantigens to CD4 + T cells remains unknown. Objectives: Here we aimed to examine the hypothesis that citrullination impacts the processing and presentation of RA autoantigens via destabilization of protein folding and modification of protease cleavage sites, altering the peptide repertoire presented by antigen-presenting cells (APCs). Methods: Using fibrinogen as a model RA autoantigen, the native and citrullinated forms were digested in vitro by a cocktail of lysosomal cathepsins (cathepsins B, S, and H) for proteolytic mapping, or incubated with monocyte-derived dendritic cells (mo-DCs) in a natural antigen processing assay (NAPA). Peptides generated by digestion with the cathepsin cocktail or presented by HLA-DR molecules on mo-DCs were then isolated and identified by mass spectrometry. Results: We found that the repertoire of peptides generated by each method was altered by citrullination. By proteolytic mapping, we detected both changes in the pattern of cathepsin cleavage and an increased number of peptides in the citrullinated samples. Utilizing NAPA, we observed the creation of newly presented peptides in the citrullinated samples in some cases, and loss of presented peptides in others (Fig. 1). Strikingly, all peptides whose presentation was destroyed by citrullination contained a citrullination site. Together these results suggest that both protease cleavage and selection of peptides by HLA-DR are impacted by citrullination. Conclusion: Citrullination alters the peptide repertoire presented by APCs. Interestingly, no citrullinated peptides were identified by NAPA, suggesting that presentation of citrulline-containing peptides to T cells may not be the primary mechanism by which tolerance is broken to citrullinated antigens. Rather, citrullination-induced destabilization of protein folding and modification of protease cleavage sites, leading to the generation of a new peptide repertoire, could play a role in activating autoreactive T cells. This mechanism could thus drive the loss of immune tolerance to the citrullinated forms of RA autoantigens. References: [1]Schellekens, G. A., Jong, B. A. de, van den Hoogen, F. H., van de Putte, L. B. & Venrooij, W. J. van. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. The Journal of Clinical Investigation 101 , 273–281 (1998). [2]Scherer, H. U., Huizinga, T. W. J., Krönke, G., Schett, G. & Toes, R. E. M. The B cell response to citrullinated antigens in the development of rheumatoid arthritis. Nature Reviews Rheumatology 14 , 157–169 (2018). [3]Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis. an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis & Rheumatism 30 , 1205–1213 (1987). Acknowledgments: Rheumatology Research Foundation and the JHU SOM Mass Spectrometry and Proteomics Core Disclosure of Interests: Ashley M. Curran: None declared, Jonathan Crawford: None declared, Erika Darrah Grant/research support from: Pfizer, Celgene, and Bristol-Myers Squibb, Consultant of: Padlock Therapeutics and Celgene
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2020-eular.1638
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1481557-6
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  • 5
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    Recurrent Germline Variant in the Cohesin Complex Gene RAD21 Predisposes Children to Lymphoblastic Leukemia and Lymphoma
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3358-3358
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3358-3358
    Abstract: Introduction: Cohesin complex genes are commonly mutated in cancer particularly in myeloid malignancies. Yet patients with germline mutations in cohesin genes, leading to cohesinopathies like Cornelia-de-Lange syndrome (CdLS) are generally not known to be tumor-prone. The complex plays a major role in chromosome alignment and segregation (Uhlmann, Nature Reviews Molecular Cell Biology, 2016), homologous recombination-driven DNA repair (Ström et al., Molecular Cell, 2004) and regulation of gene expression (Busslinger et al., Nature, 2017). To deepen the understanding of cohesin variants in cancer predisposition, we performed TRIO Sequencing in two independent pediatric cancer cohorts. Thereby, we identified a novel recurrent heterozygous germline variant in the cohesin gene RAD21 not described in CdLS patients , located in the binding domain of the cofactors WAPL and PDS5B . Methods: Whole exome sequencing (WES) in a TRIO (child-parent datasets) setting was carried out in two independent, unselected cancer cohorts (TRIO-D, n=158 (Wagener et al., European Journal of Human Genetics, 2021) and TRIO-DD, n=60). To investigate the oncogenic potential of the novel RAD21 variant molecular and functional assessment was performed focusing on potential implications on the complex. Results: The newly identified RAD21 variant at amino acid position 298 resulting in a Proline to Serine (p.P298S) and a Proline to Alanine exchange, respectively, (p.P298A) is only rarely mutated in the general population (gnomAD database n=118,479; RAD21 p.P298S MAF & lt;10 -6 and RAD21 p.P298A MAF & lt;10 -5). While both patients did not show any signs of CdLS, they both have a remarkable family history of cancer. Patient 1 (13y) was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) whose father had died from breast cancer (41y), while patient 2 (2y) presented with precursor B-cell lymphoblastic lymphoma (pB-LBL) whose uncle had died from pediatric cancer of unknown subtype (8y). To assess the influence of RAD21 p.P298S/A on the binding capacity of the complex, RAD21 variants and the wildtype (WT) were cloned and transfected into HEK293T cells, respectively. Immunoprecipitation analysis of RAD21 with the cofactors WAPL and PDS5B showed no differential binding between the WT and the variants, suggesting that RAD21 p.P298S/A does not impact the formation of the complex. Nevertheless, on a transcriptional level 83 genes were significantly differentially expressed in RAD21 p.P298S and p.P298A compared to the wildtype (fc & gt;1.5, adj. p-value & lt;0.05) with enrichment of genes in p53 signaling pathways. We further observed an increased number of γH2AX and 53BP1 co-localized foci compared to the WT (p≤0.01; Student's t-test). In line, following ionizing radiation, primary patients' samples showed increased cell cycle arrest at G2/M cell-cycle stage compared to a healthy control (p.P298S: p=0.0049 [6Gy]; p=0.0026 [10Gy] ; p.P298A: p=0.0054 [6Gy]; p=0.0006 [10Gy] ; Student's t-test). For cross-validation of the germline variant RAD21 p.P298S/A and its potential role in pediatric lymphoblastic malignancies, we analysed a third cohort of 150 children with relapsed ALL (IntReALL) for RAD21 p.P298S/A. We again identified RAD21 p.P298A in a boy (12y) with B-cell precursor acute lymphoblastic leukemia. To compare our data to a non-pediatric cancer setting, a cohort of 2300 young adults ( & lt;51 years) with cancer was mined (MASTER program). Here, one patient carrying RAD21 p.P298A with a solid tumor was identified. Therefore, amongst all cohorts, RAD21 p.P298S/A was found to be enriched in pediatric vs. adult cancers (3/479 vs. 1/2299; Fisher's exact test; p=0.018). Conclusion: Taken together, we present for the first time the potential role of RAD21 germline variants in pediatric lymphoblastic malignancies. This may shed new light on the many roles of the cohesin complex and its implication outside the typical syndromal presentation. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-150284
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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