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

Smolag Klosowska, Karolina LU orcid ; Fager Ferrari, Marcus LU orcid ; Zetterberg, Eva LU ; Leinoe, Eva ; Ek, Torben ; Blom, Anna LU orcid ; Rossing, Maria and Martin, Myriam LU (2021) In Frontiers in Immunology 12.
Abstract
Background: Hereditary 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,... (More)
Background: Hereditary 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 fromindiscriminate attack.
Methods: Sialic 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.

Results: The 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.

Conclusion: We 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. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Thrombocytopenia, GNE, Factor H, Complement activation, Sialic acid, Sialylation, High-throughput nucleotide sequencing
in
Frontiers in Immunology
volume
12
article number
777402
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85120670600
  • pmid:34858435
ISSN
1664-3224
DOI
10.3389/fimmu.2021.777402
language
English
LU publication?
yes
id
02bc3e70-4e7a-42fc-90db-56d4123a27fe
date added to LUP
2021-11-09 18:35:29
date last changed
2022-08-02 13:19:08
@article{02bc3e70-4e7a-42fc-90db-56d4123a27fe,
  abstract     = {{Background: Hereditary thrombocytopenias constitute a genetically heterogeneous<br/>cause of increased bleeding. We report a case of a 17-year-old boy suffering from<br/>severe macrothrombocytopenia throughout his life. Whole genome sequencing revealed the presence of two compound heterozygous variants in <i>GNE</i> encoding the enzyme UDP-<i>N</i>-acetyl-glucosamine-2-epimerase/<i>N</i>-acetylmannosamine kinase, crucial for sialic acid biosynthesis. Sialic acid is required for normal platelet life span, and biallelic variants in <i>GNE</i> 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 fromindiscriminate attack.<br/>Methods: Sialic acid expression and FH binding to platelets and leukocytes was<br/>evaluated by flow cytometry. The binding of FH to erythrocytes was assessed indirectly<br/>by measuring the rate of complement mediated hemolysis. Complement activation was<br/>determined by measuring levels of C3bBbP (alternative pathway), C4d (classical/lectin<br/>pathway) and soluble terminal complement complex assays.<br/><br/>Results: The 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.<br/><br/>Conclusion: We report two previously undescribed variants in GNE causing severe<br/>congenital macrothrombocytopenia in a compound heterozygous state, as a<br/>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.}},
  author       = {{Smolag Klosowska, Karolina and Fager Ferrari, Marcus and Zetterberg, Eva and Leinoe, Eva and Ek, Torben and Blom, Anna and Rossing, Maria and Martin, Myriam}},
  issn         = {{1664-3224}},
  keywords     = {{Thrombocytopenia; GNE; Factor H; Complement activation; Sialic acid; Sialylation; High-throughput nucleotide sequencing}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in <i>GNE</i>}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2021.777402}},
  doi          = {{10.3389/fimmu.2021.777402}},
  volume       = {{12}},
  year         = {{2021}},
}