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ALG12-CDG: novel glycophenotype insights endorse the molecular defect

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Abstract

Congenital disorders of glycosylation (CDG) are genetic diseases characterized by deficient synthesis (CDG type I) and/or abnormal processing (CDG type II) of glycan moieties linked to protein and lipids. The impact of the molecular defects on protein glycosylation and in turn on the clinical phenotypes of patients with CDG is not yet understood. ALG12-CDG is due to deficiency of ALG12 α1,6-mannosyltransferase that adds the eighth mannose residue on the dolichol-PP-oligosaccharide precursor in the endoplasmic reticulum. ALG12-CDG is a severe multisystem disease associated with low to deficient serum immunoglobulins and recurrent infections. We thoroughly investigated the glycophenotype in a patient with novel ALG12 variants and immunodeficiency. We analyzed serum native transferrin, as first line test for CDG and we profiled serum IgG and total serum N-glycans by a combination of consolidated (N-glycan analysis by MALDI MS) and innovative mass spectrometry-based protocols, such as GlycoWorks RapiFluor N-glycan analysis coupled with LC-ESI MS. Intact serum transferrin showed, as expected for a CDG type I defect, underoccupancy of N-glycosylation sites. Surprisingly, total serum proteins and IgG N-glycans showed some specific changes, consisting in accumulating amounts of definite high-mannose and hybrid structures. As a whole, ALG12-CDG behaves as a dual CDG (CDG-I and II defects) and it is associated with distinct, abnormal glycosylation of total serum and IgG N-glycans. Glycan profiling of target glycoproteins may endorse the molecular defect unraveling the complex clinical phenotype of CDG patients.

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Acknowledgements

The Authors thank the parents of the patient for their collaboration.

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Author notes

  1. Luisa Sturiale and Sebastiano Bianca contributed equally to this work.

Authors and Affiliations

  1. CNR, Institute for Polymers, Composites and Biomaterials, IPCB, Catania, Italy

    Luisa Sturiale, Domenico Garozzo, Angela Messina, Angelo Palmigiano, Francesca Esposito & Rita Barone

  2. Medical Genetics, Referral Centre for Rare Genetic Diseases, ARNAS Garibaldi, Catania, Italy

    Sebastiano Bianca & Chiara Barone

  3. Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Alessandra Terracciano, Emanuele Agolini & Antonio Novelli

  4. Referral Centre for Inherited Metabolic Diseases Policlinico, University of Catania, Catania, Italy

    Agata Fiumara

  5. Center for Metabolic Diseases, UZ and KU Leuven, Leuven, Belgium

    Jaak Jaeken

  6. Child Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy

    Rita Barone

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  1. Luisa Sturiale
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Contributions

Substantial contributions to conception and design: RB, SB, LS, DG. Analysis and interpretation of data: RB, SB, LS, DG, AT, EA, AM, AP, FE, CB. Drafting the article: RB, LS. Revising the article critically for important intellectual content: AF, AN, DG, JJ.

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Correspondence to Rita Barone.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee Policlinico-VE university hospital of Catania and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Sturiale, L., Bianca, S., Garozzo, D. et al. ALG12-CDG: novel glycophenotype insights endorse the molecular defect. Glycoconj J 36, 461–472 (2019). https://doi.org/10.1007/s10719-019-09890-2

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