ALG12-CDG

novel glycophenotype insights endorse the molecular defect

Luisa Sturiale, Sebastiano Bianca, Domenico Garozzo, Alessandra Terracciano, Emanuele Agolini, Angela Messina, Angelo Palmigiano, Francesca Esposito, Chiara Barone, Antonio Novelli, Agata Fiumara, Jaak Jaeken, Rita Barone

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalGlycoconjugate Journal
DOIs
Publication statusE-pub ahead of print - Sep 16 2019

Fingerprint

Congenital Disorders of Glycosylation
Glycosylation
Polysaccharides
Defects
Serum
Immunoglobulin G
Transferrin
Mannose
Lipid-Linked Proteins
Mannosyltransferases
Dolichol
Phenotype
Inborn Genetic Diseases
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Oligosaccharides
Endoplasmic Reticulum
Immunoglobulins
Blood Proteins
Mass Spectrometry
Glycoproteins

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ALG12-CDG : novel glycophenotype insights endorse the molecular defect. / Sturiale, Luisa; Bianca, Sebastiano; Garozzo, Domenico; Terracciano, Alessandra; Agolini, Emanuele; Messina, Angela; Palmigiano, Angelo; Esposito, Francesca; Barone, Chiara; Novelli, Antonio; Fiumara, Agata; Jaeken, Jaak; Barone, Rita.

In: Glycoconjugate Journal, 16.09.2019.

Research output: Contribution to journalArticle

Sturiale, L, Bianca, S, Garozzo, D, Terracciano, A, Agolini, E, Messina, A, Palmigiano, A, Esposito, F, Barone, C, Novelli, A, Fiumara, A, Jaeken, J & Barone, R 2019, 'ALG12-CDG: novel glycophenotype insights endorse the molecular defect', Glycoconjugate Journal. https://doi.org/10.1007/s10719-019-09890-2
Sturiale, Luisa ; Bianca, Sebastiano ; Garozzo, Domenico ; Terracciano, Alessandra ; Agolini, Emanuele ; Messina, Angela ; Palmigiano, Angelo ; Esposito, Francesca ; Barone, Chiara ; Novelli, Antonio ; Fiumara, Agata ; Jaeken, Jaak ; Barone, Rita. / ALG12-CDG : novel glycophenotype insights endorse the molecular defect. In: Glycoconjugate Journal. 2019.
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AU - Sturiale, Luisa

AU - Bianca, Sebastiano

AU - Garozzo, Domenico

AU - Terracciano, Alessandra

AU - Agolini, Emanuele

AU - Messina, Angela

AU - Palmigiano, Angelo

AU - Esposito, Francesca

AU - Barone, Chiara

AU - Novelli, Antonio

AU - Fiumara, Agata

AU - Jaeken, Jaak

AU - Barone, Rita

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N2 - 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.

AB - 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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