Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE

BackgroundHereditary thrombocytopenias constitute a genetically heterogeneous cause of increased bleeding. We report a case of a 17-year-old boy suffering from severe macrothrombocytopenia throughout his life. Whole genome sequencing revealed the presence of two compound heterozygous variants in GNE...

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Autores principales:	Karolina I. Smolag, Marcus Fager Ferrari, Eva Zetterberg, Eva Leinoe, Torben Ek, Anna M. Blom, Maria Rossing, Myriam Martin
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	thrombocytopenia GNE factor H complement activation sialic acid sialylation Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/020bc09b34dc4574968d73546593a7ae
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spelling	oai:doaj.org-article:020bc09b34dc4574968d73546593a7ae2021-11-09T05:53:15ZSevere Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE1664-322410.3389/fimmu.2021.777402https://doaj.org/article/020bc09b34dc4574968d73546593a7ae2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.777402/fullhttps://doaj.org/toc/1664-3224BackgroundHereditary thrombocytopenias constitute a genetically heterogeneous cause of increased bleeding. We report a case of a 17-year-old boy suffering from severe macrothrombocytopenia throughout his life. Whole genome sequencing revealed the presence of two compound heterozygous variants in GNE encoding the enzyme UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, crucial for sialic acid biosynthesis. Sialic acid is required for normal platelet life span, and biallelic variants in GNE have previously been associated with isolated macrothrombocytopenia. Furthermore, sialic acid constitutes a key ligand for complement factor H (FH), an important inhibitor of the complement system, protecting host cells from indiscriminate attack.MethodsSialic acid expression and FH binding to platelets and leukocytes was evaluated by flow cytometry. The binding of FH to erythrocytes was assessed indirectly by measuring the rate of complement mediated hemolysis. Complement activation was determined by measuring levels of C3bBbP (alternative pathway), C4d (classical/lectin pathway) and soluble terminal complement complex assays.ResultsThe proband exhibited markedly decreased expression of sialic acid on platelets and leukocytes. Consequently, the binding of FH was strongly reduced and moderate activation of the alternative and classical/lectin complement pathways was observed, together with an increased rate of erythrocyte lysis.ConclusionWe report two previously undescribed variants in GNE causing severe congenital macrothrombocytopenia in a compound heterozygous state, as a consequence of decreased platelet sialylation. The decreased sialylation of platelets, leukocytes and erythrocytes affects the binding of FH, leading to moderate complement activation and increased hemolysis.Karolina I. SmolagMarcus Fager FerrariEva ZetterbergEva LeinoeTorben EkAnna M. BlomMaria RossingMyriam MartinFrontiers Media S.A.articlethrombocytopeniaGNEfactor Hcomplement activationsialic acidsialylationImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	thrombocytopenia GNE factor H complement activation sialic acid sialylation Immunologic diseases. Allergy RC581-607
spellingShingle	thrombocytopenia GNE factor H complement activation sialic acid sialylation Immunologic diseases. Allergy RC581-607 Karolina I. Smolag Marcus Fager Ferrari Eva Zetterberg Eva Leinoe Torben Ek Anna M. Blom Maria Rossing Myriam Martin Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE
description	BackgroundHereditary thrombocytopenias constitute a genetically heterogeneous cause of increased bleeding. We report a case of a 17-year-old boy suffering from severe macrothrombocytopenia throughout his life. Whole genome sequencing revealed the presence of two compound heterozygous variants in GNE encoding the enzyme UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, crucial for sialic acid biosynthesis. Sialic acid is required for normal platelet life span, and biallelic variants in GNE have previously been associated with isolated macrothrombocytopenia. Furthermore, sialic acid constitutes a key ligand for complement factor H (FH), an important inhibitor of the complement system, protecting host cells from indiscriminate attack.MethodsSialic acid expression and FH binding to platelets and leukocytes was evaluated by flow cytometry. The binding of FH to erythrocytes was assessed indirectly by measuring the rate of complement mediated hemolysis. Complement activation was determined by measuring levels of C3bBbP (alternative pathway), C4d (classical/lectin pathway) and soluble terminal complement complex assays.ResultsThe proband exhibited markedly decreased expression of sialic acid on platelets and leukocytes. Consequently, the binding of FH was strongly reduced and moderate activation of the alternative and classical/lectin complement pathways was observed, together with an increased rate of erythrocyte lysis.ConclusionWe report two previously undescribed variants in GNE causing severe congenital macrothrombocytopenia in a compound heterozygous state, as a consequence of decreased platelet sialylation. The decreased sialylation of platelets, leukocytes and erythrocytes affects the binding of FH, leading to moderate complement activation and increased hemolysis.
format	article
author	Karolina I. Smolag Marcus Fager Ferrari Eva Zetterberg Eva Leinoe Torben Ek Anna M. Blom Maria Rossing Myriam Martin
author_facet	Karolina I. Smolag Marcus Fager Ferrari Eva Zetterberg Eva Leinoe Torben Ek Anna M. Blom Maria Rossing Myriam Martin
author_sort	Karolina I. Smolag
title	Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE
title_short	Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE
title_full	Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE
title_fullStr	Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE
title_full_unstemmed	Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE
title_sort	severe congenital thrombocytopenia characterized by decreased platelet sialylation and moderate complement activation caused by novel compound heterozygous variants in gne
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/020bc09b34dc4574968d73546593a7ae
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Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE

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