GNE variants causing autosomal recessive macrothrombocytopenia without associated muscle wasting

Revel‐Vilk, Shoshana; Shai, Ela; Turro, Ernest; Jahshan, Nivin; Hi-Am, Esti; Spectre, Galia; Daum, Hagit; Kalish, Yossef; Althaus, Karina; Greinacher, Andreas; Kaplinsky, Chaim; Izraeli, Shai; Mapeta, Rutendo; Deevi, Sri V V; Jarocha, Danuta; Ouwehand, Willem H.; Downes, Kate; Poncz, Mortimer; Varon, David; Lambert, Michele P.

doi:10.1182/blood-2018-04-845545

Cited by 49 publications

(58 citation statements)

References 15 publications

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“…107 More recent studies using WES have linked macrothrombocytopenia with AR mutations of GNE encoding UDP-N-acetylglucosamine 2-epimerase/Nacetylmannosamine kinase, a bi-functional enzyme essential for N-acetylneuraminic acid synthesis (the principle sialic acid of human platelets). [108][109][110] Interestingly GNE mutations are also a cause of myopathy and in the above studies macrothrombocytopenia was either syndromic or isolated depending on the report. Severe menorrhagia and bleeding into the corpus luteum in affected women were noteworthy.…”

Section: Desialylation and Other Glycosylation Changesmentioning

confidence: 94%

Inherited thrombocytopenias: history, advances and perspectives

Nurden

2020

Haematologica

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In the late 19 th century improvements to the light microscope led to anucleate platelets being visualized in great numbers in human blood. Early pioneers in the field of platelet research included the Canadian William Osler, a Paris hematologist, George Hayem, who performed the first accurate platelet count, and the Italian Giulio Bizzozero. 1 In 1906, James Homer Wright confirmed that platelets were produced by bone marrow megakaryocytes. 2 When, in 1951, Harrington et al. 3 observed purpura in a child of a mother with immune thrombocytopenic purpura, a maternal factor was said to be destroying the platelets. Anti-platelet antibodies were identified as the cause and platelet transfusions, immunosuppressive therapy and splenectomy became standard treatments. Acquired thrombocytopenia, often with defective platelet function, has many causes. For example, it may be an immune response linked to blood transfusions and drugs, a direct consequence of viral or bacterial infections, be the result of other hematologic disorders or be secondary to many major illnesses. However, some thrombocytopenias are inherited and Professors Jean Bernard and Jean-Pierre Soulier in Paris were pioneers in this domain, describing in 1948 what they called in French "dystrophie thrombocytaire hémorragipare congénitale", later renamed the Bernard-Soulier syndrome (BSS). 4 Strikingly, many platelets were enlarged and some were giant. A key to the molecular defect was the platelet deficit of sialic acid, a negatively charged monosaccharide terminating many of the oligosaccharides of platelet glycoproteins (GP) and

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Section: Desialylation and Other Glycosylation Changesmentioning

confidence: 94%

Inherited thrombocytopenias: history, advances and perspectives

Nurden

2020

Haematologica

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“…Patients with mutations in the GNE gene encoding for glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase, an enzyme involved in sialic acid biosynthesis (Futterer et al, 2018;Revel-Vilk et al, 2018), as well as patients with a mutation in the gene coding for the sialic acid transporter SLC35A1 (Kauskot et al, 2018) have severe thrombocytopenia and bleeding disorders. To explore the fate of platelets with defective endogenous sialylation, we next examined mice deficient in ST3Gal-IV sialyltransferase (ST3Gal-IV Δ/Δ ) that display a bleeding phenotype, a reduction in plasma vWF levels, and thrombocytopenia (Ellies et al, 2002).…”

Section: Defective Endogenous Sialylation Causes Massive Platelet Accmentioning

confidence: 99%

Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets

Deppermann

Kratofil

Peiseler

et al. 2020

Journal of Experimental Medicine

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Every day, megakaryocytes produce billions of platelets that circulate for several days and eventually are cleared by the liver. The exact removal mechanism, however, remains unclear. Loss of sialic acid residues is thought to feature in the aging and clearance of platelets. Using state-of-the-art spinning disk intravital microscopy to delineate the different compartments and cells of the mouse liver, we observed rapid accumulation of desialylated platelets predominantly on Kupffer cells, with only a few on endothelial cells and none on hepatocytes. Kupffer cell depletion prevented the removal of aged platelets from circulation. Ashwell-Morell receptor (AMR) deficiency alone had little effect on platelet uptake. Macrophage galactose lectin (MGL) together with AMR mediated clearance of desialylated or cold-stored platelets by Kupffer cells. Effective clearance is critical, as mice with an aged platelet population displayed a bleeding phenotype. Our data provide evidence that the MGL of Kupffer cells plays a significant role in the removal of desialylated platelets through a collaboration with the AMR, thereby maintaining a healthy and functional platelet compartment.

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“…In these forms, platelets are typically reduced in number and increased in size [15][16][17][18]. Finally, some IPDs induce thrombocytopenia by reducing the platelet life span, such as changes in glycosylation due to a mutated glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) gene; or impaired function of the ubiquitination, proteasome system in ANKRD26-related thrombocytopenia (ANKRD26-RT) [19][20][21][22].…”

Section: Inherited Platelet Disordersmentioning

confidence: 99%

Diagnosis of Inherited Platelet Disorders on a Blood Smear

Zaninetti

Greinacher

2020

JCM

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Inherited platelet disorders (IPDs) are rare diseases featured by low platelet count and defective platelet function. Patients have variable bleeding diathesis and sometimes additional features that can be congenital or acquired. Identification of an IPD is desirable to avoid misdiagnosis of immune thrombocytopenia and the use of improper treatments. Diagnostic tools include platelet function studies and genetic testing. The latter can be challenging as the correlation of its outcomes with phenotype is not easy. The immune-morphological evaluation of blood smears (by light- and immunofluorescence microscopy) represents a reliable method to phenotype subjects with suspected IPD. It is relatively cheap, not excessively time-consuming and applicable to shipped samples. In some forms, it can provide a diagnosis by itself, as for MYH9-RD, or in addition to other first-line tests as aggregometry or flow cytometry. In regard to genetic testing, it can guide specific sequencing. Since only minimal amounts of blood are needed for the preparation of blood smears, it can be used to characterize thrombocytopenia in pediatric patients and even newborns further. In principle, it is based on visualizing alterations in the distribution of proteins, which result from specific genetic mutations by using monoclonal antibodies. It can be applied to identify deficiencies in membrane proteins, disturbed distribution of cytoskeletal proteins, and alpha as well as delta granules. On the other hand, mutations associated with impaired signal transduction are difficult to identify by immunofluorescence of blood smears. This review summarizes technical aspects and the main diagnostic patterns achievable by this method.

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GNE variants causing autosomal recessive macrothrombocytopenia without associated muscle wasting

Cited by 49 publications

References 15 publications

Inherited thrombocytopenias: history, advances and perspectives

Inherited thrombocytopenias: history, advances and perspectives

Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets

Diagnosis of Inherited Platelet Disorders on a Blood Smear

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