Browsing by Subject "Congenital disorders of glycosylation"

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    Congenital disorder of glycosylation (PMM2-CDG) in a patient with antithrombin deficiency and severe thrombophilia
    (Elsevier, 2012-12) Morena-Barrio, María Eugenia de la; Sevivas, Teresa S.; Martínez-Martínez, Irene; Miñano, Antonia; Vicente, Vicente; Jaeken, Jaak; Corral, Javier; Medicina
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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; Rubio, Gonzalo; 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; 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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    Hypoglycosylation is a common finding in antithrombin deficiency in the absence of a SERPINC1 gene defect
    (Elsevier, 2016) Morena Barrio, María Eugenia de la; Martínez Martínez, Irene; Cos, Carmen de; Wypasek, Ewa; Roldán, Vanessa; Undas, Anetta; Sherpenzeel, Monique van; Lefeber, Dirk; Toderici, Mara; Sevivas, Teresa; España, Francisco; Jaeken, Jaak; Corral, Javier; Vicente, Vicente; Medicina
    Essentials We investigated the molecular base of antithrombin deficiency in cases without SERPINC1 defects. 27% of cases presented hypoglycosylation, transient in 62% and not restricted to antithrombin. Variations in genes involved in N-glycosylation underline this phenotype. These results support a new form of thrombophilia. Click here to listen to Dr Huntington's perspective on thrombin inhibition by the serpins. Summary: Background Since the discovery of antithrombin deficiency, 50 years ago, few new thrombophilic defects have been identified, all with weaker risk of thrombosis than antithrombin deficiency. Objective To identify new thrombophilic mechanisms. Patients/methods We studied 30 patients with antithrombin deficiency but no defects in the gene encoding this key anticoagulant (SERPINC1). Results A high proportion of these patients (8/30: 27%) had increased hypoglycosylated forms of antithrombin. All N-glycoproteins tested in these patients (α1-antitrypsin, FXI and transferrin) had electrophoretic, HPLC and Q-TOF patterns indistinguishable from those of the congenital disorders of glycosylation (rare recessive multisystem disorders). However, all except one had no mental disability. Moreover, intermittent antithrombin deficiency and hypoglycosylation was recorded in five out of these eight patients, all associated with moderate alcohol intake. Genetic analysis, including whole exome sequencing, revealed mutations in different genes involved in the N-glycosylation pathway. Conclusions Our study provides substantial and novel mechanistic insights into two disease processes, with potential implications for diagnosis and clinical care. An aberrant N-glycosylation causing a recessive or transient antithrombin deficiency is a new form of thrombophilia. Our data suggest that congenital disorders of glycosylation are probably underestimated, especially in cases with thrombosis as the main or only clinical manifestation.