Platelet Membrane Glycoprofiling in a PMM2-CDG Patient

Papazoglu, Gabriela Magali; Silvera-Ruiz, Silene M.; Salinas-Marín, Roberta; Pereira, Maria I.A.; Cubilla, Marisa A.; Pesaola, Favio; Ghione, S; Ramadan, Nehal M.; Martínez-Duncker, Iván; Asteggiano, Carla

doi:10.1590/2326-4594-jiems-2020-0030

Cited by 3 publications

(3 citation statements)

References 27 publications

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“…Based on disease pathology, one might expect a decrease in lectin binding in PMM2-CDG patient cells, due to hypoglycosylation. In fact, hypoglycosylation of serum transferrin is used to diagnose patients with CDG and reduced lectin binding has been observed in PMM2-CDG patient derived platelets, induced pluripotent stem cells and EBV transformed B cells (22,(40)(41)(42). Eventhough it was not addressed in this study, the increased lectin binding in PMM2-CDG patient monocytes that we observed could be explained by subtle differences in activation status that alter glycoprotein expression and therefore glycocalyx composition.…”

Section: Discussionmentioning

confidence: 68%

Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation

et al. 2022

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Congenital disorders of glycosylation (CDG) are inherited metabolic diseases characterized by mutations in enzymes involved in different steps of protein glycosylation, leading to aberrant synthesis, attachment or processing of glycans. Recently, immunological dysfunctions in several CDG types have been increasingly documented. Despite these observations, detailed studies on immune cell dysfunction in PMM2-CDG and other CDG types are still scarce. Studying PMM2-CDG patient immune cells is challenging due to limited availability of patient material, which is a result of the low incidence of the disease and the often young age of the subjects. Dedicated immune cell models, mimicking PMM2-CDG, could circumvent many of these problems and facilitate research into the mechanisms of immune dysfunction. Here we provide initial observations about the immunophenotype and the phagocytic function of primary PMM2-CDG monocytes. Furthermore, we assessed the suitability of two different glycosylation-impaired human monocyte models: tunicamycin-treated THP-1 monocytes and PMM2 knockdown THP-1 monocytes induced by shRNAs. We found no significant differences in primary monocyte subpopulations of PMM2-CDG patients as compared to healthy individuals but we did observe anomalous surface glycosylation patterns in PMM2-CDG patient monocytes as determined using fluorescent lectin binding. We also looked at the capacity of monocytes to bind and internalize fungal particles and found a slightly increased uptake of C. albicans by PMM2-CDG monocytes as compared to healthy monocytes. Tunicamycin-treated THP-1 monocytes showed a highly decreased uptake of fungal particles, accompanied by a strong decrease in glycosylation levels and a high induction of ER stress. In contrast and despite a drastic reduction of the PMM2 enzyme activity, PMM2 knockdown THP-1 monocytes showed no changes in global surface glycosylation levels, levels of fungal particle uptake similar to control monocytes, and no ER stress induction. Collectively, these initial observations suggest that the absence of ER stress in PMM2 knockdown THP-1 cells make this model superior over tunicamycin-treated THP-1 cells and more comparable to primary PMM2-CDG monocytes. Further development and exploitation of CDG monocyte models will be essential for future in-depth studies to ultimately unravel the mechanisms of immune dysfunction in CDG.

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Section: Discussionmentioning

confidence: 68%

Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation

et al. 2022

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“…These disorders (CDG) are genetic diseases caused by deficient glycoprotein and glycolipid glycan synthesis and attachment [81][82]. Most are multisystem disorders with variable phenotype severity and neurological involvement.…”

Section: Dystroglycanopathies and Congenital Disorders Of Glycosylationmentioning

confidence: 99%

“…Elucidation of the molecular pathological mechanisms of CDG associated with DG glycosylation abnormalities will be an important issue in understanding the mechanisms of dystroglycanopathies. Characterizing a glycoproteome profile of patients prior to and on treatment will help to better understand the changes of a plethora of glycoproteins and related clinical observations in dystroglycanopathies [81][82]86,97].…”

Section: Dystroglycanopathies and Congenital Disorders Of Glycosylationmentioning

confidence: 99%

Dystroglycanopathies: Genetic Bases of Muscular Dystrophies Due to Alteration in the O-Glycosylation of α-Dystroglycan

Cubilla

Papazoglu

Asteggiano

2023

J. inborn errors metab. screen.

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Congenital muscular dystrophies (CMDs) are inherited, progressive and heterogeneous muscle disorders. A group of CMDs are dystroglycanopathies, also called α-dystroglycanopathies, where there is an abnormal glycosylation of protein α-dystroglycan. Hypoglycosylation of α-DG results in different severities of congenital muscular dystrophies and they present with progressive muscle weakness and loss of motor functions. This article first focuses on the CMDs, their classification according to the observed symptoms or the protein involved in the resulting phenotype. We then focus on dystroglycanopathies, the importance of its correct O-glycosylation of the α-dystroglycan given its important structural function, considering the enzymes involved in said glycosylation and the phenotypes that can result, to finally address current therapeutics for these diseases with the aim of increasing current knowledge.

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Revisiting the immunopathology of congenital disorders of glycosylation: an updated review

Pascoal,

Francisco,

Mexia

et al. 2024

Front. Immunol.

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Glycosylation is a critical post-translational modification that plays a pivotal role in several biological processes, such as the immune response. Alterations in glycosylation can modulate the course of various pathologies, such as the case of congenital disorders of glycosylation (CDG), a group of more than 160 rare and complex genetic diseases. Although the link between glycosylation and immune dysfunction has already been recognized, the immune involvement in most CDG remains largely unexplored and poorly understood. In this study, we provide an update on the immune dysfunction and clinical manifestations of the 12 CDG with major immune involvement, organized into 6 categories of inborn errors of immunity according to the International Union of Immunological Societies (IUIS). The immune involvement in phosphomannomutase 2 (PMM2)-CDG - the most frequent CDG - was comprehensively reviewed, highlighting a higher prevalence of immune issues during infancy and childhood and in R141H-bearing genotypes. Finally, using PMM2-CDG as a model, we point to links between abnormal glycosylation patterns in host cells and possibly favored interactions with microorganisms that may explain the higher susceptibility to infection. Further characterizing immunopathology and unusual host-pathogen adhesion in CDG can not only improve immunological standards of care but also pave the way for innovative preventive measures and targeted glycan-based therapies that may improve quality of life for people living with CDG.

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Platelet Membrane Glycoprofiling in a PMM2-CDG Patient

Cited by 3 publications

References 27 publications

Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation

Evaluation of Cell Models to Study Monocyte Functions in PMM2 Congenital Disorders of Glycosylation

Dystroglycanopathies: Genetic Bases of Muscular Dystrophies Due to Alteration in the O-Glycosylation of α-Dystroglycan

Revisiting the immunopathology of congenital disorders of glycosylation: an updated review

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