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PubMed2026

Characterization of a series of patients with GNE-related thrombocytopenia: insights into pathogenesis, diagnosis, and treatment.

BACKGROUND: GNE-related thrombocytopenia (GNE-RT) is a very rare disorder caused by biallelic variants in GNE, which encodes a key enzyme in sialic acid biosynthesis. Patients usually present with severe thrombocytopenia and excessive bleeding. Knowledge of this condition remains limited. There are no recognized diagnostic tests for the diagnosis of GNE-RT. A previous study showed reduced platelet half-life as a mechanism of thrombocytopenia; however, it remains unclear whether the sialylation defect also impairs platelet biogenesis. OBJECTIVES: To gain insights into the clinical aspects and platelet biogenesis of GNE-RT. METHODS: We investigated 4 new GNE-RT patients (3 families). A recently standardized flow cytometry assay was used to characterize platelet sialylation. Patients' megakaryocytes were cultured to study megakaryopoiesis and proplatelet formation. A validated 3-dimensional bone marrow model was used to investigate platelet production. RESULTS: We characterized 3 novel GNE variants and demonstrated the pathogenicity of 2 variants of uncertain significance. In all individuals, platelet flow cytometry showed increased RCA-1 and ECL lectin binding and decreased MAL-II binding. Sialylation of serum transferrin showed no clear alterations. Despite the sialylation defect, patients' megakaryocytes showed preserved differentiation, maturation, and proplatelet formation. Ex vivo, megakaryocytes produced a normal number of normal-sized platelets. Two patients received eltrombopag and achieved a durable clinical response (38- and 72-month follow-up). CONCLUSION: The profound megakaryocyte sialylation defect induced by GNE variants does not affect platelet biogenesis. Platelet flow cytometry assessing RCA-1 and MAL-II binding is a reliable, simple assay for diagnosing GNE-RT. Based on a literature review, 55% of GNE-RT patients respond to thrombopoietin mimetics.

GNE gene↗

PubMed1990

Effect of immunization of ewes against prostaglandin F-2 alpha on the life-span of corpora lutea and oestrous behaviour during two breeding seasons.

Two adjuvants, Freund's complete adjuvant (FCA) and GNE (proprietary product; Intervet Ltd, The Netherlands), were used to immunize cyclic Finnish Landrace ewes (4-6/treatment) against a prostaglandin F-2 alpha-human serum albumin (PGF-HSA) conjugate. Ewes were randomized to the following treatments: (a) control-untreated, (b) control-5 mg HSA in FCA (control-HSA), (c) 5 mg PGF-HSA in FCA (FCA-5 mg), (d) 15 mg PGF-HSA in FCA (FCA-15 mg), (e) 5 mg PGF-HSA in GNE (GNE-5 mg) and (f) 15 mg PGF-HSA in GNE (GNE-15 mg). Ewes were monitored for oestrus (twice daily) and ovarian activity (progesterone concentrations in blood samples taken twice weekly) for 2 consecutive breeding seasons. In the first breeding season, the mean number of oestrous periods detected was 6.0, 5.7, 0.0, 0.2, 1.8 and 0.5 in control, control-HSA, FCA-5 mg, FCA-15 mg, GNE-5 mg and GNE-15 mg-assigned ewes, respectively [pooled standard error of difference (s.e.d.) = 1.2]. A persistent CL formed, on average, 10.0, 10.0, 29.8 and 32.5 days after primary immunization (pooled s.e.d. = 14.6) in 6/6 FCA-5 mg, 6/6 FCA-15 mg, 5/6 GNE-5 mg and 4/4 GNE-15 mg-assigned ewes, respectively; these CL were maintained for, on average, 138.7, 139.0, 127.8 and 129.0 days, respectively (pooled s.e.d. = 15.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗

PubMed2026

Identification of the Genomic Etiology of Unexplained Congenital Problems in Pediatric Patients: First Reported Case With Coffin-Siris Syndrome and Sialuria From India.

Coffin-Siris syndrome (CSS) (OMIM:614608) is a rare genetic disorder characterized by global developmental delay (GDD), speech impediment, coarse facial features, and hypoplastic or absent fifth fingernails/toenails. Genetic variants in the SMARCB1 gene are associated with CSS, benign tumors (schwannomas), and rhabdoid tumor predisposition syndrome. Genetic variants in the GNE gene are associated with the autosomal dominant sialuria (OMIM#269921), a rare inborn error of metabolism resulting in high levels of free sialic acid. Here we present case reports of two siblings: patient 1 (10 years) and patient 2 (2 years). While both siblings showed GDD and dysmorphic features such as hypotelorism and large ears, patient #1 exhibited additional phenotypes. Whole exome sequencing identified a heterozygous pathogenic variant, NM_003073.5:c.1096C>T (p.Arg366Cys), in the SMARCB1 gene in both siblings. In addition, patient 1 harbored a heterozygous likely pathogenic variant, NM_005476.7:c.2086G>A (p.Val696Met), in the GNE gene, which was absent in patient 2. The co-occurrence of the GNE variant may contribute to the increased severity of the phenotype in patient 1. This study is the first report worldwide of the co-occurrence of two extremely rare disorders. These findings highlight the complexity of genomic contributions while also emphasizing the value of genomic sequencing for congenital problems.

Coffin–Siris syndrome↗

PubMed2025

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.

As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

Humans↗