Download PDF
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
1   Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Doris Boeckelmann 
1   Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Waseem Anani
2   Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
,
Hervé Falet
2   Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
3   Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Wisconsin, United States
,
Jieqing Zhu
2   Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
4   Department of Biochemistry, Medical College of Wisconsin, Wisconsin, United States
,
Hannah Glonnegger
1   Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Hermann Full
5   Clinic for Pediatric and Adolescent Medicine, SLK-Kliniken Heilbronn, Heilbronn, Germany
,
Felicia Andresen
1   Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Miriam Erlacher
1   Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Ekkehart Lausch
6   Pediatric Genetics Section, Department of Pediatrics, University of Freiburg, Freiburg, Germany
,
Salome Fels
1   Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Brigitte Strahm
1   Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Peter Lang
7   Department of Pediatrics, Children's University Hospital, University of Tübingen, Tübingen, Germany
,
Karin M. Hoffmeister
2   Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
8   Department of Biochemistry and Medicine, Medical College of Wisconsin, Wisconsin, United States
› Author Affiliations Funding This work was supported by U.S. National Institutes of Health, National Heart, Lung, and Blood Institute grants R01 HL089224 (K.M.H.), HL126743 (H.F.), P01 HL107146 (K.M.H.), and K12 HL141954 (Program Director: K.M.H.).
› Further Information
Also available at
    Permissions and Reprints

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

Supplementary Material



Publication History

Received: 16 July 2021

Accepted: 06 December 2021

Article published online:
20 January 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Li R, Hoffmeister KM, Falet H. Glycans and the platelet life cycle. Platelets 2016; 27 (06) 505-511
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 10 Nishino I, Carrillo-Carrasco N, Argov Z. GNE myopathy: current update and future therapy. J Neurol Neurosurg Psychiatry 2015; 86 (04) 385-392
    CrossrefPubMedSearch in Google Scholar
  • 11 Enns GM, Seppala R, Musci TJ. et al. Clinical course and biochemistry of sialuria. J Inherit Metab Dis 2001; 24 (03) 328-336
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 15 Hoffmeister KM, Felbinger TW, Falet H. et al. The clearance mechanism of chilled blood platelets. Cell 2003; 112 (01) 87-97
    CrossrefPubMedSearch in Google Scholar
  • 16 Team RCR. A language and environment for statistical computing. 1.1.463 ed. Vienna: R Foundation for Statistical Computing; 2018
    Search in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 18 Murtagh F, Legendre P. Ward's hierarchical agglomerative clustering method: which algorithms implement ward's criterion?. J Classif 2014; 31 (03) 274-295
    CrossrefPubMedSearch in Google Scholar
  • 19 Pheatmap: Pretty Heatmaps. R Package Vers 2019
    PubMedSearch in Google Scholar
  • 20 Sebastien LJJ, Francois H. FactoMineR: an R Package for multivariate analysis. J Stat Softw 2008; 25 (01) 1-18
    PubMedSearch in Google Scholar
  • 21 Kassambara AMF. Factoextra: extract and visualize the results of multivariate data analyses. 2017
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar