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3. A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Author

Mingardo, Enrico, Beaman, Glenda, Grote, Philip, Nordenskjöld, Agneta, Newman, William, Woolf, Adrian S., Eckstein, Markus, Hilger, Alina C., Dworschak, Gabriel C., Rösch, Wolfgang, Ebert, Anne-Karolin, Stein, Raimund, Brusco, Alfredo, Di Grazia, Massimo, Tamer, Ali, Torres, Federico M., Hernandez, Jose L., Erben, Philipp, Maj, Carlo, Olmos, Jose M., Riancho, Jose A., Valero, Carmen, Hostettler, Isabel C., Houlden, Henry, Werring, David J., Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Buerfent, Benedikt C., Arkani, Samara, Åkesson, Elisabeth, Rotstein, Emilia, Ludwig, Michael, Holmdahl, Gundela, Giorgio, Elisa, Berettini, Alfredo, Keene, David, Cervellione, Raimondo M., Younsi, Nina, Ortlieb, Melissa, Oswald, Josef, Haid, Bernhard, Promm, Martin, Neissner, Claudia, Hirsch, Karin, Stehr, Maximilian, Schäfer, Frank-Mattias, Schmiedeke, Eberhard, Boemers, Thomas M., van Rooij, Iris A. L. M., Feitz, Wouter F. J., Marcelis, Carlo L. M., Lacher, Martin, Nelson, Jana, Ure, Benno, Fortmann, Caroline, Gale, Daniel P., Chan, Melanie M. Y., Ludwig, Kerstin U., Nöthen, Markus M., Heilmann, Stefanie, Zwink, Nadine, Jenetzky, Ekkehart, Odermatt, Benjamin, Knapp, Michael, and Reutter, Heiko

Published
2022
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7. Loss-of-function variants in myocardin cause congenital megabladder in humans and mice

Author

Houweling, Arjan C., Beaman, Glenda M., Postma, Alex V., Gainous, T. Blair, Lichtenbelt, Klaske D., Brancati, Francesco, Lopes, Filipa M., van der Made, Ingeborg, Polstra, Abeltje M., Robinson, Michael L., Wright, Kevin D., Ellingford, Jamie M., Jackson, Ashley R., Overwater, Eline, Genesio, Rita, Romano, Silvio, Camerota, Letizia, DAngelo, Emanuela, Meijers-Heijboer, Elizabeth J., Christoffels, Vincent M., McHugh, Kirk M., Black, Brian L., Newman, William G., Woolf, Adrian S., and Creemers, Esther E.

Subjects
Transcription (Genetics), Medical research, Genetic disorders, Biochemistry, Genetic research, Developmental biology, Knowledge, Smooth muscle, Gene expression, Health care industry, Wellcome Trust
Abstract

Myocardin (MYOCD) is the founding member of a class of transcriptional coactivators that bind the serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies, and to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis., Introduction Urinary tract and kidney malformations often result in termination of pregnancy after being detected on ultrasound screening, and these anomalies are also a major cause of renal failure in [...]

Published
2019
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9. Effects of heat shock, hypoxia, post-mortem interval and glioma disease state on heat shock gene HSPA expression

Author

Beaman, Glenda Marie

Subjects
363.25, QR Microbiology, RB Pathology
Abstract

Heat shock protein 70 (HSPA/HSP70) gene expression is induced by a wide range of cellular stress conditions. This study investigated HSPA/HSP70 expression in human cell lines exposed to hypoxic conditions, in cancerous and non-cancerous brain tissue specimens from 18 patients (gliomas and normal conditions), and in post mortem rat brain samples exposed to heat shock. Three human glioma cell lines were chosen for this study, each representing various types of glioma: (astrocytoma, oligodendroglioma and glioblastoma), with a normal human astrocyte cell line used as a control. In addition, 18 clinical brain tissue samples were also examined. HSPA RNA transcripts and proteins were examined in these samples using qRT-PCR, immunofluorescence and flow cytometry techniques. The average HSPA mRNA copy numbers detected in glioblastoma tissue were 1.8 and 8.8 fold higher respectively than in lower grade glioma and control tissues, which is suggestive of a grade related transcription profile. Similar patterns of grade related expression were also observed in corresponding cell lines. The percentage of cells showing positive for HSPA protein in normal cell lines increased from 0 to 33% immediately after exposure to hypoxia, and gradually declined to 11% 24 h after treatment. However, the effects of hypoxia were marginal in glioma cells, due to the already elevated levels of HSPA. Although hypoxia induced HSPA expression in normal cells, it did not achieve the same level of induction in cancer cells, suggesting that there are other factors which contribute to the induction of HSPA. These results suggest that HSPA is induced in cancer cells, not only by hypoxia, but also by other factors. In addition, this study indicated for the first time that HSPA expression in glioma cells may possibly be grade related, and thus may have value as a prognostic marker. However a greater sample size is needed to validate such findings. This study showed that HSPA is expressed at low levels in normal brain tissue, but was more highly expressed in brain tissue subjected to mild heat shock. The levels of HSPA transcripts in heat shocked post mortem brain tissue showed a marked increase in HSPA expression. GAPDH was used as a control gene for these studies, and exhibited a consistent level of expression in normal and tumourous cell lines and tissue samples under normal and hypoxic conditions, and also in post mortem tissues exposed to heat shock. For Homo sapiens GAPDH, the average transcript numbers for normal and tumourous cell lines and brain tissue samples were approximately 145,000 copies per sample. For Rattus norvegicus GAPDH, levels were higher than for human samples, at an average of 268,300 copies per sample. The consistency of these results confirms that GAPDH was a suitable candidate gene for the purpose of this study. Early in the post-mortem period, HSPA is expressed more highly in tissues subjected to single and multiple heat shocks compared to controls. However, later post-mortem intervals of between 3 - 24 h demonstrated inconsistent and irregular results, with no predictive or reproducible patterns. Therefore, although there is demonstrable de novo expression of HSPA in post mortem brain tissue in response to heat shock, it is difficult to predict the full parameters of this induction, probably as a result of other forms of cellular stress affecting these tissues under our experimental methodology. These initial studies indicate that the use of HSPA with the methodologies employed here are not suitable as an accurate indicator of post-mortem interval.

Published
2012

10. Neurogenic defects underlie functional bladder outflow tract obstruction associated with biallelic variants inLRIG2

Author

Grenier, Celine, primary, Lopes, Filipa M., additional, Cueto-González, Anna M, additional, Rovira-Moreno, Eulàlia, additional, Gander, Romy, additional, Jarvis, Benjamin W, additional, McCloskey, Karen D., additional, Gurney, Alison M., additional, Beaman, Glenda M., additional, Newman, William G., additional, Woolf, Adrian S., additional, and Roberts, Neil A., additional

Published
2022
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11. Germline intergenic duplications at Xq26.1 underlie Bazex–Dupré–Christol basal cell carcinoma susceptibility syndrome

Author

Liu, Yanshan, primary, Banka, Siddharth, additional, Huang, Yingzhi, additional, Hardman-Smart, Jonathan, additional, Pye, Derek, additional, Torrelo, Antonio, additional, Beaman, Glenda M., additional, Kazanietz, Marcelo G., additional, Baker, Martin J., additional, Ferrazzano, Carlo, additional, Shi, Chenfu, additional, Orozco, Gisela, additional, Eyre, Stephen, additional, van Geel, Michel, additional, Bygum, Anette, additional, Fischer, Judith, additional, Miedzybrodzka, Zosia, additional, Abuzahra, Faris, additional, Rübben, Albert, additional, Cuvertino, Sara, additional, Ellingford, Jamie M., additional, Smith, Miriam J., additional, Evans, D. Gareth, additional, Weppner-Parren, Lizelotte J.M.T., additional, van Steensel, Maurice A.M., additional, Chaudhary, Iskander H., additional, Mangham, D. Chas, additional, Lear, John T., additional, Paus, Ralf, additional, Frank, Jorge, additional, Newman, William G., additional, and Zhang, Xue, additional

Published
2022
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13. Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder

Author

Beaman, Glenda M., primary, Lopes, Filipa M., additional, Hofmann, Aybike, additional, Roesch, Wolfgang, additional, Promm, Martin, additional, Bijlsma, Emilia K., additional, Patel, Chirag, additional, Akinci, Aykut, additional, Burgu, Berk, additional, Knijnenburg, Jeroen, additional, Ho, Gladys, additional, Aufschlaeger, Christina, additional, Dathe, Sylvia, additional, Voelckel, Marie Antoinette, additional, Cohen, Monika, additional, Yue, Wyatt W., additional, Stuart, Helen M., additional, Mckenzie, Edward A., additional, Elvin, Mark, additional, Roberts, Neil A., additional, Woolf, Adrian S., additional, and Newman, William G., additional

Published
2022
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15. Germline intergenic duplications at Xq26.1 underlie Bazex-Dupre-Christol syndrome, an inherited basal cell carcinoma susceptibility condition

Author

Liu, Yanshan, primary, Banka, Siddharth, additional, Huang, Yingzhi, additional, Hardman-Smart, Jonathan, additional, Pye, Derek, additional, Torrelo, Antonio, additional, Beaman, Glenda M., additional, Kazanietz, Marcelo G., additional, Bake, Martin J., additional, Ferrazzano, Carlo, additional, Shi, Chenfu, additional, Orozco, Gisela, additional, Eyre, Stephen, additional, van Geel, Michel, additional, Bygum, Anette, additional, Fischer, Judith, additional, Miedzybrodzka, Zosia, additional, Abuzahra, Faris, additional, Ruebben, Albert, additional, Cuvertino, Sara, additional, Ellingford, Jamie M., additional, Smith, Miriam J., additional, Evans, Gareth, additional, Weppner-Parren, Lizelotte J.M.T, additional, van Steensel, Maurice A.M., additional, Chaudhary, Iskander H., additional, Mangham, Chas, additional, Lear, John T., additional, Paus, Ralf, additional, Frank, Jorge, additional, Newman, William G., additional, and Zhang, Xue, additional

Published
2022
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17. Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations

Author

Hochberg, Irit, primary, Demain, Leigh A.M., additional, Richer, Julie, additional, Thompson, Kyle, additional, Urquhart, Jill E., additional, Rea, Alessandro, additional, Pagarkar, Waheeda, additional, Rodríguez-Palmero, Agustí, additional, Schlüter, Agatha, additional, Verdura, Edgard, additional, Pujol, Aurora, additional, Quijada-Fraile, Pilar, additional, Amberger, Albert, additional, Deutschmann, Andrea J., additional, Demetz, Sandra, additional, Gillespie, Meredith, additional, Belyantseva, Inna A., additional, McMillan, Hugh J., additional, Barzik, Melanie, additional, Beaman, Glenda M., additional, Motha, Reeya, additional, Ng, Kah Ying, additional, O’Sullivan, James, additional, Williams, Simon G., additional, Bhaskar, Sanjeev S., additional, Lawrence, Isabella R., additional, Jenkinson, Emma M., additional, Zambonin, Jessica L., additional, Blumenfeld, Zeev, additional, Yalonetsky, Sergey, additional, Oerum, Stephanie, additional, Rossmanith, Walter, additional, Yue, Wyatt W., additional, Zschocke, Johannes, additional, Munro, Kevin J., additional, Battersby, Brendan J., additional, Friedman, Thomas B., additional, Taylor, Robert W., additional, O’Keefe, Raymond T., additional, and Newman, William G., additional

Published
2021
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22. Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves.

Author

Chan, Melanie M. Y., Sadeghi-Alavijeh, Omid, Lopes, Filipa M., Hilger, Alina C., Stanescu, Horia C., Voinescu, Catalin D., Beaman, Glenda M., Newman, William G., Zaniew, Marcin, Weber, Stefanie, Yee Mang Ho, Connolly, John O., Wood, Dan, Maj, Carlo, Stuckey, Alexander, Kousathanas, Athanasios, Kleta, Robert, Woolf, Adrian S., Bockenhauer, Detlef, and Levine, Adam P.

Published
2022
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24. Comparison of in Silico Strategies to Prioritize Rare Genomic Variants Impacting RNA Splicing for the Diagnosis of Genomic Disorders

Author

Rowlands, Charlie, primary, Thomas, Huw B, additional, Lord, Jenny, additional, Wai, Htoo A, additional, Arno, Gavin, additional, Beaman, Glenda, additional, Sergouniotis, Panagiotis, additional, Gomes-Silva, Beatriz, additional, Campbell, Christopher, additional, Gossan, Nicole, additional, Hardcastle, Claire, additional, Webb, Kevin, additional, O’Callaghan, Christopher, additional, Hirst, Robert A, additional, Ramsden, Simon, additional, Jones, Elizabeth, additional, -Smith, Jill Clayton, additional, Webster, Andrew R, additional, Douglas, Andrew GL, additional, O’Keefe, Raymond T, additional, Newman, William G, additional, Baralle, Diana, additional, Black, Graeme CM, additional, and Ellingford, Jamie M, additional

Published
2021
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25. SLC20A1 is involved in urinary tract and urorectal development

Author

Rieke, Johanna Magdalena, Zhang, Rong, Braun, Doreen, Yilmaz, Öznur, Japp, Anna S., Lopes, Filipa M., Pleschka, Michael, Hilger, Alina C., Schneider, Sophia, Newman, William G., Beaman, Glenda M., Nordenskjöld, Agneta, Ebert, Anne-Karoline, Promm, Martin, Rösch, Wolfgang H., Stein, Raimund, Hirsch, Karin, Schäfer, Frank-Mattias, Schmiedeke, Eberhard, Boemers, Thomas M., Lacher, Martin, Kluth, Dietrich, Gosemann, Jan-Hendrik, Anderberg, Magnus, Barker, Gillian, Holmdahl, Gundela, Läckgren, Göran, Keene, David, Cervellione, Raimondo M., Giorgio, Elisa, Di Grazia, Massimo, Feitz, Wouter F. J., Marcelis, Carlo L. M., Rooij, Iris A. L. M. van, Bökenkamp, Arend, Beckers, Goedele M. A., Keegan, Catherine E., Sharma, Amit, Dakal, Tikam Chand, Wittler, Lars, Grote, Phillip, Zwink, Nadine, Jenetzky, Ekkehart, Brusco, Alfredo, Thiele, Holger, Ludwig, Michael, Schweizer, Ulrich, Woolf, Adrian S., Odermatt, Benjamin, and Reutter, Heiko

Subjects
animal structures, ddc:570, embryonic structures, ddc:610
Abstract

Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.

Published
2020

26. A Dominantly Inherited 5′ UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer

Author

Evans, D Gareth R, van Veen, Elke M, Byers, Helen J, Wallace, Andrew J, Ellingford, Jamie M, Beaman, Glenda, Santoyo-Lopez, Javier, Aitman, Timothy J., Eccles, Diana M, Lalloo, Fiona I, Smith, Miriam J, and Newman, William G

Subjects
Adult, Aged, 80 and over, BRCA2 Protein, Ovarian Neoplasms, endocrine system diseases, familial breast and ovarian cancer, BRCA1 Protein, promoter hypermethylation, Breast Neoplasms, DNA Methylation, Middle Aged, BRCA1, Article, Epigenesis, Genetic, secondary epimutation, Humans, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, 5' Untranslated Regions, Promoter Regions, Genetic, epigenetic, Germ-Line Mutation, Aged
Abstract

Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5' UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.-107A>T in the BRCA1 5' UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5' UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.

Published
2018

28. Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders

Author

Rowlands, Charlie, primary, Thomas, Huw, additional, Lord, Jenny, additional, Wai, Htoo, additional, Arno, Gavin, additional, Beaman, Glenda, additional, Sergouniotis, Panagiotis, additional, Silva, Beatriz Gomes, additional, Campbell, Christopher, additional, Gossan, Nicole, additional, Hardcastle, Claire, additional, Webb, Kevin, additional, Callaghan, Christopher O, additional, Hirst, Robert, additional, Ramsden, Simon, additional, Jones, Elizabeth, additional, Smith, Jill Clayton, additional, Webster, Andrew, additional, Douglas, Andrew, additional, Keefe, Raymond T O, additional, Newman, William, additional, Baralle, Diana, additional, Black, Graeme, additional, and Ellingford, Jamie, additional

Published
2020
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29. Expanding the genotypic spectrum of TXNL4A variants in Burn‐McKeown syndrome.

Author

Wood, Katherine A., Ellingford, Jamie M., Thomas, Huw B., Douzgou, Sofia, Beaman, Glenda M., Hobson, Emma, Prescott, Katrina, O'Keefe, Raymond T., and Newman, William G.

Subjects
RNA splicing, GENOTYPES, BINDING sites, TRANSCRIPTION factors, TELEOLOGY
Abstract

The developmental disorder Burn‐McKeown Syndrome (BMKS) is characterised by choanal atresia and specific craniofacial features. BMKS is caused by biallelic variants in the pre‐messenger RNA splicing factor TXNL4A. Most patients have a loss‐of‐function variant in trans with a 34‐base pair (bp) deletion (type 1 Δ34) in the promoter region. Here, we identified two patients with BMKS. One individual has a TXNL4A c.93_94delCC, p.His32Argfs *21 variant combined with a type 1 Δ34 promoter deletion. The other has an intronic TXNL4A splice site variant (c.258‐3C>G) and a type 1 Δ34 promoter deletion. We show the c.258‐3C>G variant and a previously reported c.258‐2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region. We propose that additional variants affecting critical transcription factor binding nucleotides within the 22 bp repeated motif could be relevant to BMKS aetiology. Finally, our data emphasises the need to analyse the non‐coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation. [ABSTRACT FROM AUTHOR]

Published
2022
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30. Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects.

Author

Pagnamenta, Alistair T., Jackson, Adam, Perveen, Rahat, Beaman, Glenda, Petts, Gemma, Gupta, Asheeta, Hyder, Zerin, Chung, Brian Hon‐Yin, Kan, Anita Sik‐Yau, Cheung, Ka Wang, Kerstjens‐Frederikse, Wilhelmina S., Abbott, Kristin M., Elpeleg, Orly, Taylor, Jenny C., Banka, Siddharth, and Ta‐Shma, Asaf

Subjects
CONGENITAL heart disease, VENTRICULAR septal defects, POLYCYSTIC kidney disease, HEART abnormalities, PHENOTYPES, CONGENITAL disorders
Abstract

Only two families have been reported with biallelic TMEM260 variants segregating with structural heart defects and renal anomalies syndrome (SHDRA). With a combination of genome, exome sequencing and RNA studies, we identified eight individuals from five families with biallelic TMEM260 variants. Variants included one multi‐exon deletion, four nonsense/frameshifts, two splicing changes and one missense change. Together with the published cases, analysis of clinical data revealed ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse‐shoe kidneys (1/12) and renal cysts (1/12) in patients. Three pregnancies were terminated on detection of severe congenital anomalies. Six patients died between the ages of 6 weeks and 5 years. Using a range of stringencies, carrier frequency for SHDRA was estimated at 0.0007–0.007 across ancestries. In conclusion, this study confirms the genetic basis of SHDRA, expands its known mutational spectrum and clarifies its clinical features. We demonstrate that SHDRA is a severe condition associated with substantial mortality in early childhood and characterised by congenital cardiac malformations with a variable renal phenotype. [ABSTRACT FROM AUTHOR]

Published
2022
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31. SLC20A1 Is Involved in Urinary Tract and Urorectal Development

Author

Rieke, Johanna Magdalena, primary, Zhang, Rong, additional, Braun, Doreen, additional, Yilmaz, Öznur, additional, Japp, Anna S., additional, Lopes, Filipa M., additional, Pleschka, Michael, additional, Hilger, Alina C., additional, Schneider, Sophia, additional, Newman, William G., additional, Beaman, Glenda M., additional, Nordenskjöld, Agneta, additional, Ebert, Anne-Karoline, additional, Promm, Martin, additional, Rösch, Wolfgang H., additional, Stein, Raimund, additional, Hirsch, Karin, additional, Schäfer, Frank-Mattias, additional, Schmiedeke, Eberhard, additional, Boemers, Thomas M., additional, Lacher, Martin, additional, Kluth, Dietrich, additional, Gosemann, Jan-Hendrik, additional, Anderberg, Magnus, additional, Barker, Gillian, additional, Holmdahl, Gundela, additional, Läckgren, Göran, additional, Keene, David, additional, Cervellione, Raimondo M., additional, Giorgio, Elisa, additional, Di Grazia, Massimo, additional, Feitz, Wouter F. J., additional, Marcelis, Carlo L. M., additional, Van Rooij, Iris A. L. M., additional, Bökenkamp, Arend, additional, Beckers, Goedele M. A., additional, Keegan, Catherine E., additional, Sharma, Amit, additional, Dakal, Tikam Chand, additional, Wittler, Lars, additional, Grote, Phillip, additional, Zwink, Nadine, additional, Jenetzky, Ekkehart, additional, Brusco, Alfredo, additional, Thiele, Holger, additional, Ludwig, Michael, additional, Schweizer, Ulrich, additional, Woolf, Adrian S., additional, Odermatt, Benjamin, additional, and Reutter, Heiko, additional

Published
2020
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32. Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders.

Author

Rowlands, Charlie, Thomas, Huw B., Lord, Jenny, Wai, Htoo A., Arno, Gavin, Beaman, Glenda, Sergouniotis, Panagiotis, Gomes-Silva, Beatriz, Campbell, Christopher, Gossan, Nicole, Hardcastle, Claire, Webb, Kevin, O'Callaghan, Christopher, Hirst, Robert A., Ramsden, Simon, Jones, Elizabeth, Clayton-Smith, Jill, Webster, Andrew R., Genomics England Research Consortium, and Ambrose, J. C.

Subjects
RNA splicing, DIAGNOSIS, DIAGNOSIS methods, FUNCTIONAL analysis
Abstract

The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being 'pathogenic' or 'benign' is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as 'pathogenic' or 'likely pathogenic'; one in five of these cases could lead to new or refined diagnoses. [ABSTRACT FROM AUTHOR]

Published
2021
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33. A homozygous missense variant in CHRM3 associated with familial urinary bladder disease

Author

Beaman, Glenda M., primary, Galatà, Gabriella, additional, Teik, Keng W., additional, Urquhart, Jill E., additional, Aishah, Ali, additional, O'Sullivan, James, additional, Bhaskar, Sanjeev S., additional, Wood, Katherine A., additional, Thomas, Huw B., additional, O'Keefe, Raymond T., additional, Woolf, Adrian S., additional, Stuart, Helen M., additional, and Newman, William G., additional

Published
2019
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34. Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction

Author

Kolvenbach, Caroline M., primary, Dworschak, Gabriel C., additional, Frese, Sandra, additional, Japp, Anna S., additional, Schuster, Peggy, additional, Wenzlitschke, Nina, additional, Yilmaz, Öznur, additional, Lopes, Filipa M., additional, Pryalukhin, Alexey, additional, Schierbaum, Luca, additional, van der Zanden, Loes F.M., additional, Kause, Franziska, additional, Schneider, Ronen, additional, Taranta-Janusz, Katarzyna, additional, Szczepańska, Maria, additional, Pawlaczyk, Krzysztof, additional, Newman, William G., additional, Beaman, Glenda M., additional, Stuart, Helen M., additional, Cervellione, Raimondo M., additional, Feitz, Wouter F.J., additional, van Rooij, Iris A.L.M., additional, Schreuder, Michiel F., additional, Steffens, Martijn, additional, Weber, Stefanie, additional, Merz, Waltraut M., additional, Feldkötter, Markus, additional, Hoppe, Bernd, additional, Thiele, Holger, additional, Altmüller, Janine, additional, Berg, Christoph, additional, Kristiansen, Glen, additional, Ludwig, Michael, additional, Reutter, Heiko, additional, Woolf, Adrian S., additional, Hildebrandt, Friedhelm, additional, Grote, Phillip, additional, Zaniew, Marcin, additional, Odermatt, Benjamin, additional, and Hilger, Alina C., additional

Published
2019
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36. Inherited BRCA1 epimutation as a novel cause of breast and ovarian cancer

Author

Evans, D. Gareth R., primary, van Veen, Elke M., additional, Byers, Helen J., additional, Wallace, Andrew J., additional, Ellingford, Jamie M., additional, Beaman, Glenda, additional, Santoyo-Lopez, Javier, additional, Aitman, Timothy J., additional, Eccles, Diana M., additional, Lalloo, Fiona I., additional, Smith, Miriam J., additional, and Newman, William G., additional

Published
2018
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37. ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development

Author

Zhang, Rong, primary, Knapp, Michael, additional, Suzuki, Kentaro, additional, Kajioka, Daiki, additional, Schmidt, Johanna M., additional, Winkler, Jonas, additional, Yilmaz, Öznur, additional, Pleschka, Michael, additional, Cao, Jia, additional, Kockum, Christina Clementson, additional, Barker, Gillian, additional, Holmdahl, Gundela, additional, Beaman, Glenda, additional, Keene, David, additional, Woolf, Adrian S., additional, Cervellione, Raimondo M., additional, Cheng, Wei, additional, Wilkins, Simon, additional, Gearhart, John P., additional, Sirchia, Fabio, additional, Di Grazia, Massimo, additional, Ebert, Anne-Karolin, additional, Rösch, Wolfgang, additional, Ellinger, Jörg, additional, Jenetzky, Ekkehart, additional, Zwink, Nadine, additional, Feitz, Wout F., additional, Marcelis, Carlo, additional, Schumacher, Johannes, additional, Martinón-Torres, Federico, additional, Hibberd, Martin Lloyd, additional, Khor, Chiea Chuen, additional, Heilmann-Heimbach, Stefanie, additional, Barth, Sandra, additional, Boyadjiev, Simeon A., additional, Brusco, Alfredo, additional, Ludwig, Michael, additional, Newman, William, additional, Nordenskjöld, Agneta, additional, Yamada, Gen, additional, Odermatt, Benjamin, additional, and Reutter, Heiko, additional

Published
2017
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38. Effects of heat shock, hypoxia, post-mortem interval and glioma disease state on heat shock gene HSPA expression

Author

Beaman, Glenda Marie

Subjects
B130, C500
Abstract

Heat shock protein 70 (HSPA/HSP70) gene expression is induced by a wide range of cellular stress conditions. This study investigated HSPA/HSP70 expression in human cell lines exposed to hypoxic conditions, in cancerous and non-cancerous brain tissue specimens from 18 patients (gliomas and normal conditions), and in post mortem rat brain samples exposed to heat shock.\ud Three human glioma cell lines were chosen for this study, each representing various types of glioma: (astrocytoma, oligodendroglioma and glioblastoma), with a normal human astrocyte cell line used as a control. In addition, 18 clinical brain tissue samples were also examined. HSPA RNA transcripts and proteins were examined in these samples using qRT-PCR, immunofluorescence and flow cytometry techniques. \ud The average HSPA mRNA copy numbers detected in glioblastoma tissue were 1.8 and 8.8 fold higher respectively than in lower grade glioma and control tissues, which is suggestive of a grade related transcription profile. Similar patterns of grade related expression were also observed in corresponding cell lines. The percentage of cells showing positive for HSPA protein in normal cell lines increased from 0 to 33% immediately after exposure to hypoxia, and gradually declined to 11% 24 h after treatment. However, the effects of hypoxia were marginal in glioma cells, due to the already elevated levels of HSPA. Although hypoxia induced HSPA expression in normal cells, it did not achieve the same level of induction in cancer cells, suggesting that there are other factors which contribute to the induction of HSPA. These results suggest that HSPA is induced in cancer cells, not only by hypoxia, but also by other factors. In addition, this study indicated for the first time that HSPA expression in glioma cells may possibly be grade related, and thus may have value as a prognostic marker. However a greater sample size is needed to validate such findings. \ud This study showed that HSPA is expressed at low levels in normal brain tissue, but was more highly expressed in brain tissue subjected to mild heat shock. The levels of HSPA transcripts in heat shocked post mortem brain tissue showed a marked increase in HSPA expression. \ud GAPDH was used as a control gene for these studies, and exhibited a consistent level of expression in normal and tumourous cell lines and tissue samples under normal and hypoxic conditions, and also in post mortem tissues exposed to heat shock. For Homo sapiens GAPDH, the average transcript numbers for normal and tumourous cell lines and brain tissue samples were approximately 145,000 copies per sample. For Rattus norvegicus GAPDH, levels were higher than for human samples, at an average of 268,300 copies per sample. The consistency of these results confirms that GAPDH was a suitable candidate gene for the purpose of this study.\ud Early in the post-mortem period, HSPA is expressed more highly in tissues subjected to single and multiple heat shocks compared to controls. However, later post-mortem intervals of between 3 - 24 h demonstrated inconsistent and irregular results, with no predictive or reproducible patterns. Therefore, although there is demonstrable de novo expression of HSPA in post mortem brain tissue in response to heat shock, it is difficult to predict the full parameters of this induction, probably as a result of other forms of cellular stress affecting these tissues under our experimental methodology. These initial studies indicate that the use of HSPA with the methodologies employed here are not suitable as an accurate indicator of post-mortem interval.

39. ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development

Author

Fabio Sirchia, Adrian S. Woolf, Jonas Winkler, Chiea Chuen Khor, Simon Wilkins, Benjamin Odermatt, Johanna M. Schmidt, Wolfgang Rösch, Johannes Schumacher, Ekkehart Jenetzky, Öznur Yilmaz, Heiko Reutter, Christina Clementson Kockum, Michael Ludwig, Simeon A. Boyadjiev, Gillian Barker, David Keene, Federico Martinón-Torres, Anne K. Ebert, Jia Cao, Daiki Kajioka, William G. Newman, Rong Zhang, Sandra Barth, Jörg Ellinger, Nadine Zwink, Michael Knapp, John P. Gearhart, Michael Pleschka, Carlo Marcelis, Glenda M. Beaman, Stefanie Heilmann-Heimbach, Kentaro Suzuki, Gen Yamada, Agneta Nordenskjöld, Wout F.J. Feitz, Alfredo Brusco, Gundela Holmdahl, Raimondo M. Cervellione, Wei Cheng, Massimo Di Grazia, Martin L. Hibberd, Zhang, Rong, Knapp, Michael, Suzuki, Kentaro, Kajioka, Daiki, Schmidt, Johanna M., Winkler, Jona, Yilmaz, Öznur, Pleschka, Michael, Cao, Jia, Kockum, Christina Clementson, Barker, Gillian, Holmdahl, Gundela, Beaman, Glenda, Keene, David, Woolf, Adrian S., Cervellione, Raimondo M., Cheng, Wei, Wilkins, Simon, Gearhart, John P., Sirchia, Fabio, DI GRAZIA, Massimo, Ebert, Anne Karolin, Rösch, Wolfgang, Ellinger, Jörg, Jenetzky, Ekkehart, Zwink, Nadine, Feitz, Wout F., Marcelis, Carlo, Schumacher, Johanne, Martinón Torres, Federico, Hibberd, Martin Lloyd, Khor, Chiea Chuen, Heilmann Heimbach, Stefanie, Barth, Sandra, Boyadjiev, Simeon A., Brusco, Alfredo, Ludwig, Michael, Newman, William, Nordenskjöld, Agneta, Yamada, Gen, Odermatt, Benjamin, and Reutter, Heiko

Subjects
0301 basic medicine, medicine.medical_specialty, Pathology, Mesenchyme, Urinary system, Organogenesis, LIM-Homeodomain Proteins, Locus (genetics), 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, bladder extrophy, Article, Pronephros, Mesoderm, 03 medical and health sciences, Mice, BEEC, bladder extrophy, urinary tract development, ISL1, Genotype, medicine, Animals, Humans, Protein Isoforms, Genetic Predisposition to Disease, BEEC, Urinary Tract, Gene, Zebrafish, Genetics, Multidisciplinary, Bladder Exstrophy, Gene Expression Regulation, Developmental, ISL1, medicine.disease, Embryo, Mammalian, urinary tract development, Bladder exstrophy, 030104 developmental biology, medicine.anatomical_structure, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Larva, Medical genetics, Female, Transcription Factors, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10−08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10−19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

Published
2017
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40. Hereditary renal cancer patient and public involvement group: A collaborative, consensus decision process to develop a communication tool for patient use.

Author

Colvin E, Ng S, Hepworth J, Hepworth J, Hartley T, Godfrey N, Tricker K, Rothwell J, Beaman G, and Woodward ER

Abstract

Patient and public involvement (PPI) must be more frequently embedded within clinical research to ensure translational outcomes are patient-led and meet patient needs. Active partnerships with patients and public groups are an important opportunity to hear patient voices, understand patient needs, and inform future research avenues. A hereditary renal cancer (HRC) PPI group was developed with the efforts of patient participants ( n = 9), pooled from recruits within the early detection for HRC pilot study, working in collaboration with researchers and healthcare professionals ( n = 8). Patient participants had HRC conditions including Von Hippel-Lindau ( n = 3) and Hereditary Leiomyomatosis and Renal Cell Carcinoma ( n = 5), and public participants included two patient Trustees ( n = 2) from VHL UK & Ireland Charity. Discussions among the enthusiastic participants guided the development of a novel patient information sheet for HRC patients. This communication tool was designed to aid patients when informing family members about their diagnoses and the wider implications for relatives, a gap identified by participants within group discussions. While this partnership was tailored for a specific HRC patient and public group, the process implemented can be employed for other hereditary cancer groups and could be transferable within other healthcare settings., Competing Interests: The authors and members of the ACED ELECTRIC study involved in the development of this PPI group and the PIS declare no conflicts of interest with respect to the development of the PPI group, PIS nor the preparation and writing of the manuscript., (© The Author(s) 2023.)

Published
2023
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