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4. N-linked glycosylation of the M-protein variable region:glycoproteogenomics reveals a new layer of personalized complexity in multiple myeloma

Author

Langerhorst, Pieter, Baerenfaenger, Melissa, Kulkarni, Purva, Nadal, Simon, Wijnands, Charissa, Post, Merel A., Noori, Somayya, Vanduijn, Martijn M., Joosten, Irma, Dejoie, Thomas, Van Gool, Alain J., Gloerich, Jolein, Lefeber, Dirk J., Wessels, Hans J.C.T., Jacobs, Joannes F.M., Langerhorst, Pieter, Baerenfaenger, Melissa, Kulkarni, Purva, Nadal, Simon, Wijnands, Charissa, Post, Merel A., Noori, Somayya, Vanduijn, Martijn M., Joosten, Irma, Dejoie, Thomas, Van Gool, Alain J., Gloerich, Jolein, Lefeber, Dirk J., Wessels, Hans J.C.T., and Jacobs, Joannes F.M.

Abstract

Multiple myeloma (MM) is a plasma cell malignancy characterized by a monoclonal expansion of plasma cells that secrete a characteristic M-protein. This M-protein is crucial for diagnosis and monitoring of MM in the blood of patients. Recent evidence has emerged suggesting that N-glycosylation of the M-protein variable (Fab) region contributes to M-protein pathogenicity, and that it is a risk factor for disease progression of plasma cell disorders. Current methodologies lack the specificity to provide a site-specific glycoprofile of the Fab regions of M-proteins. Here, we introduce a novel glycoproteogenomics method that allows detailed M-protein glycoprofiling by integrating patient specific Fab region sequences (genomics) with glycoprofiling by glycoproteomics. Glycoproteogenomics was used for the detailed analysis of de novo N-glycosylation sites of M-proteins. First, Genomic analysis of the M-protein variable region was used to identify de novo N-glycosylation sites. Subsequently glycopeptide analysis with LC-MS/MS was used for detailed analysis of the M-protein glycan sites. Genomic analysis uncovered a more than two-fold increase in the Fab Light Chain N-glycosylation of M-proteins of patients with Multiple Myeloma compared to Fab Light Chain N-glycosylation of polyclonal antibodies from healthy individuals. Subsequent glycoproteogenomics analysis of 41 patients enrolled in the IFM 2009 clinical trial revealed that the majority of the Fab N-glycosylation sites were fully occupied with complex type glycans, distinguishable from Fc region glycans due to high levels of sialylation, fucosylation and bisecting structures. Together, glycoproteogenomics is a powerful tool to study de novo Fab N-glycosylation in plasma cell dyscrasias.

Published
2024

5. N-linked glycosylation of the M-protein variable region: glycoproteogenomics reveals a new layer of personalized complexity in multiple myeloma.

Author

Langerhorst, Pieter, Baerenfaenger, Melissa, Kulkarni, Purva, Nadal, Simon, Wijnands, Charissa, Post, Merel A., Noori, Somayya, vanDuijn, Martijn M., Joosten, Irma, Dejoie, Thomas, van Gool, Alain J., Gloerich, Jolein, Lefeber, Dirk J., Wessels, Hans J.C.T., and Jacobs, Joannes F.M.

Subjects
*MULTIPLE myeloma, *PLASMA cell diseases, *PLASMA cells, *DISEASE risk factors, *GLYCOSYLATION, *CD38 antigen, *GLYCANS
Abstract

Multiple myeloma (MM) is a plasma cell malignancy characterized by a monoclonal expansion of plasma cells that secrete a characteristic M-protein. This M-protein is crucial for diagnosis and monitoring of MM in the blood of patients. Recent evidence has emerged suggesting that N-glycosylation of the M-protein variable (Fab) region contributes to M-protein pathogenicity, and that it is a risk factor for disease progression of plasma cell disorders. Current methodologies lack the specificity to provide a site-specific glycoprofile of the Fab regions of M-proteins. Here, we introduce a novel glycoproteogenomics method that allows detailed M-protein glycoprofiling by integrating patient specific Fab region sequences (genomics) with glycoprofiling by glycoproteomics. Glycoproteogenomics was used for the detailed analysis of de novo N-glycosylation sites of M-proteins. First, Genomic analysis of the M-protein variable region was used to identify de novo N-glycosylation sites. Subsequently glycopeptide analysis with LC-MS/MS was used for detailed analysis of the M-protein glycan sites. Genomic analysis uncovered a more than two-fold increase in the Fab Light Chain N-glycosylation of M-proteins of patients with Multiple Myeloma compared to Fab Light Chain N-glycosylation of polyclonal antibodies from healthy individuals. Subsequent glycoproteogenomics analysis of 41 patients enrolled in the IFM 2009 clinical trial revealed that the majority of the Fab N-glycosylation sites were fully occupied with complex type glycans, distinguishable from Fc region glycans due to high levels of sialylation, fucosylation and bisecting structures. Together, glycoproteogenomics is a powerful tool to study de novo Fab N-glycosylation in plasma cell dyscrasias. [ABSTRACT FROM AUTHOR]

Published
2024
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10. N-linked glycosylation of the M-protein variable region: Glycoproteogenomics reveals a new layer of personalized complexity in multiple myeloma

Author

Langerhorst, Pieter, primary, Baerenfaenger, Melissa, additional, Kulkarni, Purva, additional, Nadal, Simon, additional, Wijnands, Charissa, additional, Post, Merel A., additional, Noori, Somayya, additional, vanDuijn, Martijn M., additional, Joosten, Irma, additional, Dejoie, Thomas, additional, van Gool, Alain J., additional, Gloerich, Jolein, additional, Lefeber, Dirk J., additional, Wessels, Hans J.C.T., additional, and Jacobs, Joannes F.M., additional

Published
2023
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13. Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings

Author

Wilson, Matthew P., primary, Garanto, Alejandro, additional, Pinto e Vairo, Filippo, additional, Ng, Bobby G., additional, Ranatunga, Wasantha K., additional, Ventouratou, Marina, additional, Baerenfaenger, Melissa, additional, Huijben, Karin, additional, Thiel, Christian, additional, Ashikov, Angel, additional, Keldermans, Liesbeth, additional, Souche, Erika, additional, Vuillaumier-Barrot, Sandrine, additional, Dupré, Thierry, additional, Michelakakis, Helen, additional, Fiumara, Agata, additional, Pitt, James, additional, White, Susan M., additional, Lim, Sze Chern, additional, Gallacher, Lyndon, additional, Peters, Heidi, additional, Rymen, Daisy, additional, Witters, Peter, additional, Ribes, Antonia, additional, Morales-Romero, Blai, additional, Rodríguez-Palmero, Agustí, additional, Ballhausen, Diana, additional, de Lonlay, Pascale, additional, Barone, Rita, additional, Janssen, Mirian C.H., additional, Jaeken, Jaak, additional, Freeze, Hudson H., additional, Matthijs, Gert, additional, Morava, Eva, additional, and Lefeber, Dirk J., additional

Published
2021
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16. Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5

Author

Linders, Peter T.A., primary, Gerretsen, Eveline C.F., additional, Ashikov, Angel, additional, Vals, Mari-Anne, additional, de Boer, Rinse, additional, Revelo, Natalia H., additional, Arts, Richard, additional, Baerenfaenger, Melissa, additional, Zijlstra, Fokje, additional, Huijben, Karin, additional, Raymond, Kimiyo, additional, Muru, Kai, additional, Fjodorova, Olga, additional, Pajusalu, Sander, additional, Õunap, Katrin, additional, Beest, Martin ter, additional, Lefeber, Dirk, additional, and van den Bogaart, Geert, additional

Published
2020
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20. Biallelic variants in SLC35C1as a cause of isolated short stature with intellectual disability

Author

Knapp, Karen M., Luu, Rebecca, Baerenfaenger, Melissa, Zijlstra, Fokje, Wessels, Hans J. C. T., Jenkins, Danielle, Lefeber, Dirk J., Neas, Katherine, and Bicknell, Louise S.

Abstract

Variants in SLC35C1underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all caused by an inability to generate key fucosylated molecules due to a defective transport of GDP-fucose into the Golgi. Here we report the use of exome sequencing to identify biallelic variants in SLC35C1(c.501_503delCTT, p.(Phe168del) and c.891T > G, p.(Asn297Lys)) in an individual with short stature and ID. Retrospective clinical examination based on the genetic findings revealed increased otitis media as the only immunological feature present in this child. Biochemical analysis of patient serum identified a clear but mild decrease in protein fucosylation. Modelling all described missense mutations on a SLC35C1 protein model showed pathogenic substitutions localise to close to the dimer interface, providing insight into the possible pathophysiology of non-synonymous causative variants identified in patients. Our evidence confirms this is the second family presenting with only a subset of features and broadens the clinical presentation of this syndrome. Of note, both families segregated a common allele (p.Phe168del), suggesting there could be an associated genotype-phenotype relationship for specific variants. Based on two out of 14 reported families not presenting with the characteristic features of SLC35C1-CDG, we suggest there is clinical utility in considering this gene in patients with short stature and ID.

Published
2020
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