Dissecting the transcriptional program of phosphomannomutase 2-deficient cells: Lymphoblastoide B cell lines as a valuable model for congenital disorders of glycosylation studies
Por:
Parrado A, Rubio G, Serrano M, De la Morena-Barrio ME, Ibáñez-Micó S, Ruiz-Lafuente N, Schwartz-Albiez R, Esteve-Solé A, Alsina L, Corral J and Hernández-Caselles T
Publicada:
19 mar 2022
Ahead of Print:
1 dic 2021
Categoría:
Biochemistry
Resumen:
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.
Filiaciones:
Parrado A:
Immunology Service, Virgen de la Arrixaca University Clinic Hospital, IMIB-Arrixaca, Murcia, Spain
Rubio G:
Department of Biochemistry and Molecular Biology (B) and Immunology, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain
Serrano M:
Department of Pediatric Neurology, Institute of Pediatric Research-Hospital Sant Joan de Déu, U-703 Center for Biomedical Research on Rare Diseases, CIBERER, Barcelona, Spain
De la Morena-Barrio ME:
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Spain
Ibáñez-Micó S:
Pediatric Neurology Unit, Virgen de la Arrixaca University Clinic Hospital, Murcia, Spain
Ruiz-Lafuente N:
Immunology Service, Virgen de la Arrixaca University Clinic Hospital, IMIB-Arrixaca, Murcia, Spain
Schwartz-Albiez R:
CLS Cell Line Service, Eppelheim, Germany
Esteve-Solé A:
Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain
Alsina L:
Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain
Corral J:
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Spain
Hernández-Caselles T:
Department of Biochemistry and Molecular Biology (B) and Immunology, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain
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