Novel GNE Gene Variants Associated with Severe Congenital Thrombocytopenia and Platelet Sialylation Defect

Barbara Zieger; Doris Boeckelmann; Waseem Anani; Hervé Falet; Jieqing Zhu; Hannah Glonnegger; Hermann Full; Felicia Andresen; Miriam Erlacher; Ekkehart Lausch; Salome Fels; Brigitte Strahm; Peter Lang; Karin M. Hoffmeister

doi:10.1055/s-0041-1742207

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2022; 122(07): 1139-1146
DOI: 10.1055/s-0041-1742207

Cellular Haemostasis and Platelets

Novel GNE Gene Variants Associated with Severe Congenital Thrombocytopenia and Platelet Sialylation Defect

Barbara Zieger

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

,

Doris Boeckelmann

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

,

Waseem Anani

²Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States

,

Hervé Falet

²Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States

³Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Wisconsin, United States

,

Jieqing Zhu

²Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States

⁴Department of Biochemistry, Medical College of Wisconsin, Wisconsin, United States

,

Hannah Glonnegger

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

,

Hermann Full

⁵Clinic for Pediatric and Adolescent Medicine, SLK-Kliniken Heilbronn, Heilbronn, Germany

,

Felicia Andresen

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

,

Miriam Erlacher

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

,

Ekkehart Lausch

⁶Pediatric Genetics Section, Department of Pediatrics, University of Freiburg, Freiburg, Germany

,

Salome Fels

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

,

Brigitte Strahm

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

,

Peter Lang

⁷Department of Pediatrics, Children's University Hospital, University of Tübingen, Tübingen, Germany

,

Karin M. Hoffmeister

²Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States

⁸Department of Biochemistry and Medicine, Medical College of Wisconsin, Wisconsin, United States

› Institutsangaben

Abstract

The GNE gene encodes an enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically associated with Nonaka myopathy and sialuria, following an autosomal recessive and autosomal dominant inheritance pattern. Reports show that single GNE variants cause severe thrombocytopenia without muscle weakness. Using panel sequencing, we identified two novel compound heterozygous variants in GNE in a young girl with life-threatening bleedings, severe congenital thrombocytopenia, and a platelet secretion defect. Both variants are located in the nucleotide-binding site of the N-acetylmannosamin kinase domain of GNE. Lectin array showed decreased α-2,3-sialylation on platelets, consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. Hematopoietic stem cell transplantation (HSCT) normalized platelet counts. This is the first report of an HSCT in a patient with an inherited GNE defect leading to normal platelet counts.

Keywords

platelet disorders - congenital thrombocytopenia - GNE - lectin

Volltext

Referenzen

References
1 Hinderlich S, Weidemann W, Yardeni T, Horstkorte R, Huizing M. UDP-GlcNAc 2-epimerase/ManNAc Kinase (GNE): a master regulator of sialic acid synthesis. Top Curr Chem 2015; 366: 97-137
2 Lee-Sundlov MM, Stowell SR, Hoffmeister KM. Multifaceted role of glycosylation in transfusion medicine, platelets, and red blood cells. J Thromb Haemost 2020; 18 (07) 1535-1547
3 King SL, Joshi HJ, Schjoldager KT. et al. Characterizing the O-glycosylation landscape of human plasma, platelets, and endothelial cells. Blood Adv 2017; 1 (07) 429-442
4 Kotzé HF, van Wyk V, Badenhorst PN, Heyns AD, Roodt JP, Lötter MG. Influence of platelet membrane sialic acid and platelet-associated IgG on ageing and sequestration of blood platelets in baboons. Thromb Haemost 1993; 70 (04) 676-680
5 Li R, Hoffmeister KM, Falet H. Glycans and the platelet life cycle. Platelets 2016; 27 (06) 505-511
6 Sørensen AL, Rumjantseva V, Nayeb-Hashemi S. et al. Role of sialic acid for platelet life span: exposure of beta-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor-expressing liver macrophages and hepatocytes. Blood 2009; 114 (08) 1645-1654
7 Deppermann C, Kratofil RM, Peiseler M. et al. Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets. J Exp Med 2020; 217 (04) e20190723
8 Celeste FV, Vilboux T, Ciccone C. et al. Mutation update for GNE gene variants associated with GNE myopathy. Hum Mutat 2014; 35 (08) 915-926
9 Mori-Yoshimura M, Hayashi YK, Yonemoto N. et al. Nationwide patient registry for GNE myopathy in Japan. Orphanet J Rare Dis 2014; 9: 150
10 Nishino I, Carrillo-Carrasco N, Argov Z. GNE myopathy: current update and future therapy. J Neurol Neurosurg Psychiatry 2015; 86 (04) 385-392
11 Enns GM, Seppala R, Musci TJ. et al. Clinical course and biochemistry of sialuria. J Inherit Metab Dis 2001; 24 (03) 328-336
12 Leroy JG, Seppala R, Huizing M. et al. Dominant inheritance of sialuria, an inborn error of feedback inhibition. Am J Hum Genet 2001; 68 (06) 1419-1427
13 Revel-Vilk S, Shai E, Turro E. et al. GNE variants causing autosomal recessive macrothrombocytopenia without associated muscle wasting. Blood 2018; 132 (17) 1851-1854
14 Neubauer K, Boeckelmann D, Koehler U. et al. Hereditary neuralgic amyotrophy in childhood caused by duplication within the SEPT9 gene: a family study. Cytoskeleton (Hoboken) 2019; 76 (01) 131-136
15 Hoffmeister KM, Felbinger TW, Falet H. et al. The clearance mechanism of chilled blood platelets. Cell 2003; 112 (01) 87-97
16 Team RCR. A language and environment for statistical computing. 1.1.463 ed. Vienna: R Foundation for Statistical Computing; 2018
17 Ritchie ME, Phipson B, Wu D. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43 (07) e47
18 Murtagh F, Legendre P. Ward's hierarchical agglomerative clustering method: which algorithms implement ward's criterion?. J Classif 2014; 31 (03) 274-295
19 Pheatmap: Pretty Heatmaps. R Package Vers 2019
20 Sebastien LJJ, Francois H. FactoMineR: an R Package for multivariate analysis. J Stat Softw 2008; 25 (01) 1-18
21 Kassambara AMF. Factoextra: extract and visualize the results of multivariate data analyses. 2017
22 Martinez J, Nguyen LD, Hinderlich S. et al. Crystal structures of N-acetylmannosamine kinase provide insights into enzyme activity and inhibition. J Biol Chem 2012; 287 (17) 13656-13665
23 Futterer J, Dalby A, Lowe GC. et al; UK GAPP Study Group. Mutation in GNE is associated with severe congenital thrombocytopenia. Blood 2018; 132 (17) 1855-1858
24 Li X, Li Y, Lei M. et al. Congenital thrombocytopenia associated with GNE mutations in twin sisters: a case report and literature review. BMC Med Genet 2020; 21 (01) 224
25 Effertz K, Hinderlich S, Reutter W. Selective loss of either the epimerase or kinase activity of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase due to site-directed mutagenesis based on sequence alignments. J Biol Chem 1999; 274 (40) 28771-28778
26 Park EI, Mi Y, Unverzagt C, Gabius HJ, Baenziger JU. The asialoglycoprotein receptor clears glycoconjugates terminating with sialic acid alpha 2,6GalNAc. Proc Natl Acad Sci U S A 2005; 102 (47) 17125-17129

Zusatzmaterial

Supplementary Material