Novel mutation SLFN14 T853fs associated with inherited macrothrombocytopenia

SLFN14-related inherited thrombocytopenia (SLFN14-related IT) is a hereditary disorder involving ribosomopathy and platelet dysfunction. Affected patients exhibit significant bleeding tendencies. To date, five affected pedigrees have been reported, all harboring mutations within the "ATPase associated with diverse cellular activities" (AAA) domain. In this study, we identified a novel T853fs variant located in the "helicase" domain. SLFN14 expression was markedly reduced in platelets from the patients and in Meg-01 cells transfected with T853fs plasmid. Functional assays revealed a defection of T853fs variant in both arachidonic acid (AA)-induced aggregation and fibrinogen-induced adhesion. Unlike previously reported mutations in the AAA domain, which significantly upregulate ribosomal protein genes and mitochondrial translation pathways, the T853fs mutation identified in this study did not affect mitochondrial translation. Immunofluorescence assay showed that T853fs variant exhibited diffuse cytoplasmic localization. Further RNA sequencing (RNA-seq) analysis revealed the significant regulation of T853fs mutation on pathways related to ion channels and dense granule, which are crucial to platelet function. In conclusion, this study identifies a new SLFN14 mutation and highlights the phenotypic diversity of SLFN14-RT.