Abstract Number: PB1447
Meeting: ISTH 2020 Congress
Background: The GNE gene encodes for a kinase with a key role in sialic acid biosynthesis and its mutations are classically associated with myopathy and sialuria, displaying an autosomal recessive and autosomal dominant inheritance pattern, respectively. Nevertheless, in a few recent cases, GNE variants have be associated with thrombocytopenia both with and without muscle weakness.
Aims: We present a two-year-old child of a consanguineous couple with a significant platelet count reduction, intending to disclose the molecular causes underlying the disease.
Methods: The proband and his family members, including both the parents and the two healthy sisters, underwent whole exome sequencing and Sanger sequencing analysis, respectively. We assessed variant pathogenicity by western blot, protein 3D-structure analysis and sialic acid assays to evaluate the mutation effect both on protein structure and function.
Results: The patient was found to carry a novel homozygous variant, c.1724C>G (p.Thr575Arg) of the GNE gene. No candidate variants were identified in the other known thrombocytopenia-causing genes. The pedigree analysis confirmed segregation within the family in accordance with an autosomal recessive pattern. The western blots of proband’s cell culture unveiled a considerable reduction in the protein expression level in comparison to the wild-type control, suggesting that the mutant protein is unstable. Moreover, the pathogenic effect of p.Thr575Arg was further supported by the altered three-dimensional structure of GNE ATP pocket and a defective sialylation, which could affect platelet production and/or survival in the patient.
Conclusions: Considering the growing cases similar to our proband reported in the literature, we are confident that including GNE among the genes associated to inherited thrombocytopenias could significantly contribute to understanding the role of GNE in inherited thrombocytopenia, as well as patients’ appropriate molecular diagnosis and clinical management.
To cite this abstract in AMA style:Persico I, Bottega R, Faletra F, Giangregorio T, D'Adamo P, Bianco AM, Pastore A, Grotto P, Gabelli M, Biffi A, Burlina A, Marzollo A, Savoia A. New Clues to GNE Gene Role in the Pathogenesis of Inherited Thrombocytopenias [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/new-clues-to-gne-gene-role-in-the-pathogenesis-of-inherited-thrombocytopenias/. Accessed December 5, 2021.
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