A novel variant of the CYCS gene causes thrombocytopenia through deregulated Tumor Necrosis Factor signaling

Mutations in the CYCS gene have been linked to the development of mild autosomal dominant thrombocytopenia, which is included in the group of inherited thrombocytopenias. Here we report the identification of a novel heterozygous variant of the CYCS gene (c.292T>C (p.Tyr98His)) found in a Greek family with thrombocytopenia.

Its functional role in several cellular processes has been examined to delineate the mechanisms underlying the thrombocytopenic phenotype of the patients. The novel variant has been associated with increased megakaryocyte apoptosis, and has led to decreased ATP levels through the reduced superoxidase activity of Cytc in megakaryocytic cells. RNA-Seq has provided information about the effect of the CYCS variant on Tumor Necrosis Factor (TNF) signaling, revealing a dual mechanism through the negative enrichment of TNF via nuclear factor kappa B (NFKB) signaling in combination with the positive enrichment of the TNF via p38 .