85 - Oral Communication
Mechanisms of Disease II
Feb. 26, 2021, 1:45 p.m. - 3:15 p.m., Lausanne


The Glycosylation Nexus Enigma: new clues to the role of the GNE gene in the pathogenesis of inherited thrombocytopenia in both isolated and myopathy-associated forms
I. Persico1, R. Bottega1, F. Faletra1, D. Simoncini2, G. Robustelli2, A. M. Bianco1, A. Pastore3, M. Agosti2, P. Grotto4, M. Gabelli5, A. Biffi5, A. Burlina5, M. Marinoni2, A. Marzollo5, P. Noris6, A. Savoia1, Presenter: I. Persico1 (1Trieste, 2Varese, 3London, 4Treviso, 5Padua, 6Pavia)

Background and Objective
The GNE gene encodes a kinase with a key role in sialic acid biosynthesis and its mutations are classically linked to sialuria and GNE myopathy. Nevertheless, in a few recent cases, GNE variants have been associated with inherited thrombocytopenia (IT) both with and without muscle weakness. Herein, we present two young probands (P1, P2) of unrelated consanguineous couples with significant platelet count reduction and no myopathy signs hitherto, aiming to disclose the molecular causes underlying the disease.
P1 and his family members underwent whole exome and Sanger sequencing, respectively. Variant pathogenicity was assessed by western blot, protein 3D-structure analysis and sialic acid assays to evaluate the mutation effect on protein structure and function. Since P2 is a more recent case, he was investigated only by whole exome sequencing and his variant role was predicted via protein 3D-structure modelling. Further analyses are currently ongoing.
P1 and P2 were found to carry two novel homozygous variants, c.1724C>G (p.Thr575Arg) and c.1546_1547delGTinsAG (p.Val516Arg) of the GNE gene, respectively. No candidate variants were identified in the other known ITs-causing genes. In P1, pedigree analysis confirmed segregation within the family in accordance with an autosomal recessive pattern, and western blots of his cell culture unveiled a considerable reduction in protein expression, suggesting mutant protein instability. Moreover, P1 was reported for defective sialylation, which could affect platelet production and/or survival. Both p.Thr575Arg and p.Val516Arg were assumed to alter the three-dimensional structure of the GNE ATP pocket, further supporting their pathogenic effect.
Consistently with our cases, severe thrombocytopenia has been found in 5 other families with GNE anomalies in the ATP pocket and no evidence of GNE myopathy, even in adulthood. The same mutations were not reported for any of the 950 known patients with GNE myopathy. Thus, our data claim a possible nexus between the ATP pocket location of the variants, the protein domain disfunction and decreased platelet counts. Although further studies are required, including GNE among the genes associated to ITs could significantly contribute to understanding the role of GNE in these disorders, as well as patients’ appropriate molecular diagnosis and clinical management.
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