Mutation in GNE is associated with severe congenital thrombocytopenia

Fütterer, Jane Wong; Dalby, Amanda; Lowe, Gillian; Johnson, Benjamin C.; Simpson, Michael A.; Jayashree, Muralidharan; Williams, M.; Watson, Steve P.; Morgan, Neil V.

doi:10.1182/blood-2018-04-847798

Cited by 50 publications

(51 citation statements)

References 15 publications

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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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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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“…Thrombocytopenia has been reported in a small number of patients with GNE myopathy [25,26], but one study determined the occurrence of thrombocytopenia was similar to that of the general population in Japan [10,22]. Congenital thrombocytopenia has also been reported in families with compound heterozygous GNE mutations, and although the etiology still needs to be determined, the authors suggested hyposialylation of platelets leading to increased platelet clearance as a possible mechanism [26,27].…”

Section: Clinical Manifestations Of Gne Myopathymentioning

confidence: 99%

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic Brimmed^vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.

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“…Theoretically, vaginal bleeding may occur in pregnant women who have a tendency to bleed. Some case reports have indicated a relationship between thrombocytopenia and GNE myopathy [26] or GNE mutations [27]. Platelet desialylation level is reportedly associated with thrombocytopenia in septic patients [28].…”

Section: Discussionmentioning

confidence: 99%

Pregnancy in GNE Myopathy Patients: A Nationwide Repository Survey in Japan

Yoshioka

Miyasaka

Okubo

et al. 2020

Preprint

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Background: GNE myopathy is an autosomal recessive adult-onset distal myopathy. While a few case reports have described the progression of GNE myopathy during pregnancy, none have examined progression after delivery or obstetric complications. Objective: This study aimed to reveal maternal complications, newborn complications, and the impact of pregnancy on disease progression in GNE myopathy patients. Methods: We conducted a questionnaire survey on pregnancy, delivery, and newborns involving female GNE myopathy patients who are currently registered in a national registry in Japan.Results: The response rate for the questionnaire survey was 60.0% (72/120). Of the 72 respondents, 44 (61.1%) had pregnancy experience (average, 1.8 pregnancies; 53 pregnancies before onset and 28 after onset). The incidence of threatened abortion was 26.9% among post-onset pregnancies, which was higher compared to those of the general Japanese population (p=0.03). No other maternal or infant complications were commonly observed. Over 80% were unaware of changes in disease progression during pregnancy or after delivery, while 19.0% experienced disease exacerbation within a year after delivery. Six patients developed myopathy within a year after delivery, while none developed myopathy during pregnancy.Conclusions: There were no serious maternal or newborn complications, and subjective progression did not differ during or after delivery in the majority of GNE myopathy patients. However, our findings suggest the importance of considering the possibility of threatened abortion and disease progression after delivery.

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Mutation in GNE is associated with severe congenital thrombocytopenia

Cited by 50 publications

References 15 publications

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

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

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

Pregnancy in GNE Myopathy Patients: A Nationwide Repository Survey in Japan

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