Browsing by Subject "PMM2-CDG"

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    Dissecting the transcriptional program of phosphomannomutase 2-deficient cells: Lymphoblastoide B cell lines as a valuable model for congenital disorders of glycosylation studies
    (2021) Parrado González, Antonio; Serrano Gimaré, M.; De La Morena Barrio, M. E.; Ibañez Micó, S.; Ruiz Lafuente, N.; Schwartz-albiez, R.; Esteve Solé, A.; Alsina Manrique De Lara, L.; Corral de la Calle, Javier; Hernández Caselles, Trinidad; Rubio Pedraza, Gonzalo; Bioquímica y Biología Molecular B e Inmunología
    Congenital disorders of glycosylation (CDG) include 150 disorders constituting in genetically and clinically heterogeneous diseases, showing significant glycoprotein hypoglycosylation that leads to pathological consequences on multiple organs and systems whose underlying mechanisms are not yet understood. A few cellular and animal models have been used to study specific CDG characteristics, although they have given limited information due to the few CDG mutations tested and the still missing comprehensive molecular and cellular basic research. Here, we provide specific gene expression profiles, based on ribonucleic acid (RNA) microarray analysis, together with some biochemical and cellular characteristics of a total of nine control Epstein– Barr virus-transformed lymphoblastoid B cell lines (B-LCL) and 13 CDG B-LCL from patients carrying severe mutations in the phosphomannomutase 2 (PMM2) gene, strong serum protein hypoglycosylation and neurological symptoms. Significantly dysregulated genes in PMM2-CDG cells included those regulating stress responses, transcription factors, glycosylation, motility, cell junction and, importantly, those related to development and neuronal differentiation and synapse, such as carbonic anhydrase 2 (CA2) and ADAM23. PMM2-CDG-associated biological consequences involved the unfolded protein response, RNA metabolism and the endoplasmic reticulum, Golgi apparatus and mitochondria components. Changes in the transcriptional and CA2 protein levels are consistent with the CDG physiopathology. These results demonstrate the global transcriptional impact in phosphomannomutase 2-deficient cells, reveal CA2 as a potential cellular biomarker and confirm B-LCL as an advantageous model for CDG studies.
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    Dissecting the transcriptional program of phosphomannomutase 2-deficient cells: Lymphoblastoide B cell lines as a valuable model for congenital disorders of glycosylation studies
    (Oxford University Press, 2022) Parrado, Antonio; Serrano, Mercedes; De la Morena-Barrio, María Eugenia; Ibáñez-Micó, Salvador; Ruiz-Lafuente, Natalia; Schwartz-Albiez, Reinhard; Esteve-Solé, Ana; Alsina, Laia; Corral, Javier; Hernández Caselles, Trinidad; Rubio Pedraza, Gonzalo; Bioquímica y Biología Molecular B e Inmunología
    Congenital disorders of glycosylation (CDG) include 150 disorders constituting in genetically and clinically heterogeneous diseases, showing significant glycoprotein hypoglycosylation that leads to pathological consequences on multiple organs and systems whose underlying mechanisms are not yet understood. A few cellular and animal models have been used to study specific CDG characteristics, although they have given limited information due to the few CDG mutations tested and the still missing comprehensive molecular and cellular basic research. Here, we provide specific gene expression profiles, based on ribonucleic acid (RNA) microarray analysis, together with some biochemical and cellular characteristics of a total of nine control Epstein– Barr virus-transformed lymphoblastoid B cell lines (B-LCL) and 13 CDG B-LCL from patients carrying severe mutations in the phosphomannomutase 2 (PMM2) gene, strong serum protein hypoglycosylation and neurological symptoms. Significantly dysregulated genes in PMM2-CDG cells included those regulating stress responses, transcription factors, glycosylation, motility, cell junction and, importantly, those related to development and neuronal differentiation and synapse, such as carbonic anhydrase 2 (CA2) and ADAM23. PMM2-CDG-associated biological consequences involved the unfolded protein response, RNA metabolism and the endoplasmic reticulum, Golgi apparatus and mitochondria components. Changes in the transcriptional and CA2 protein levels are consistent with the CDG physiopathology. These results demonstrate the global transcriptional impact in phosphomannomutase 2-deficient cells, reveal CA2 as a potential cellular biomarker and confirm B-LCL as an advantageous model for CDG studies.
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    GPI-anchor and GPI-anchored protein expression in PMM2-CDG patients
    (2013) Morena-Barrio, María Eugenia de la; Corral, Javier; García-López, Roberto; Martínez-Martínez, Irene; Pérez-Dueñas, Belén; Altisent, Carmen; Sevivas, Teresa; Kristensen, Soren; Guillén-Navarro, Encarna; Miñano, Antonia; Vicente, Vicente; Jaeken, Jaak; Lozano, María Luisa; Hernández Caselles, Trinidad; Medicina
    Background: Mutations in PMM2 impair phosphomannomutase-2 activity and cause the most frequent congenital disorder of glycosylation, PMM2-CDG. Mannose-1-phosphate, that is deficient in this disorder, is also implicated in the biosynthesis of glycosylphosphatidyl inositol (GPI) anchors. Objective: To evaluate whether GPI-anchor and GPI-anchored proteins are defective in PMM2-CDG patients. Methods: The expression of GPI-anchor and seven GPI-anchored proteins was evaluated by flow cytometry in different cell types from twelve PMM2-CDG patients. Additionally, neutrophil CD16 and plasma hepatic proteins were studied by Western blot. Transferrin glycoforms were evaluated by HPLC. Results: Patients and controls had similar surface expression of GPI-anchor and most GPI-anchored proteins. Nevertheless, patients displayed a significantly diminished binding of two anti-CD16 antibodies (3G8 and KD1) to neutrophils and also of anti-CD14 (61D3) to monocytes. Interestingly, CD16 immunostaining and asialotransferrin levels significantly correlated with patients' age. Analysis by flow cytometry of CD14 with MΦP9, and CD16 expression in neutrophils by Western blot using H-80 ruled out deficiencies of these antigens. Conclusions: PMM2 mutations do not impair GPI-anchor or GPI-anchored protein expression. However, the glycosylation anomalies caused by PMM2 mutations might affect the immunoreactivity of monoclonal antibodies and lead to incorrect conclusions about the expression of different proteins, including GPI-anchored proteins. Neutrophils and monocytes are sensitive to PMM2 mutations, leading to abnormal glycosylation in immune receptors, which might potentially affect their affinity to their ligands, and contribute to infection. This study also confirms less severe hypoglycosylation defects in older PMM2-CDG patients.
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    International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up
    (WILEY, 2019) Altassan, Ruqaiah; Péanne, Romain; Jaeken, Jaak; Barone, Rita; Borgel, Delphine; Brasil, Sandra; Cassiman, David; Cechova, Anna; Coman, David; Corral, Javier; Correia, Joana; Morena-Barrio, María Eugenia de la; Lonlay, Pascale de; Dos Reis, Vanessa; Ferreira, Carlos R; Fiumara, Agata; Francisco, Rita; Freeze, Hudson; Funke, Simone; Gardeitchik, Thatjana; Matthijs, Gert; Girad, Muriel; Giros, Marisa; Grünewald, Stephanie; Honzik, Tomas; Hutter, Marlen; Krasnewich, Donna; Lam, Christina; Lee, Joy; Lefeber, Dirk; Marques-de-Silva, Dorinda; Martinez, Antonio F; Moravej, Hossein; Õunap, Katrin; Pascoal, Carlota; Pascreau, Tiffany; Patterson, Marc; Quelhas, Dulce; Raymond, Kimiyo; Sarkhail, Peymaneh; Schiff, Manuel; Seroczyńska, Małgorzata; Serrano, Mercedes; Seta, Nathalie; Sykut-Cegielska, Jolanta; Thiel, Christian; Tort, Federic; Vals, Mari-Anne; Videira, Paula; Witters, Peter; Zeevaert, Renate; Morava, Eva; Hernández Caselles, Trinidad; Bioquímica y Biología Molecular B e Inmunología
    Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.