Modeling ANKRD26 5'-UTR mutation-related thrombocytopenia.

Mutations in the 5'-untranslated region (5'-UTR) of ankyrin repeat domain-containing protein 26 (ANKRD26) are associated with hereditary thrombocytopenia 2 (THC2). However, the causative role of these mutations and the mechanisms underlying THC2 are not fully established. Here, we report, for the first time, that zebrafish carrying a deletion of two nucleotides (Δ2) in the 5'-UTR of ankrd26 recapitulate some of the key laboratory features of THC2. ankrd26ku6 (homozygous for the Δ2 deletion in the 5'-UTR) fish larvae exhibited significantly increased expression of ankrd26 mRNA and protein. Adult ankrd26ku6 fish exhibited spontaneous thrombocytopenia. Furthermore, the thrombocytes from ankrd26ku6 fish showed enhanced ability to adhere and aggregate on a collagen surface under flow. Proteomic profiling demonstrated marked upregulation of Ninjurin 1 in young thrombocytes from ankrd26ku6 fish compared with those from wild-type controls. The ankrd26ku6 fish with a homozygous nacre allele developed myelodysplastic syndrome at old age. ANKRD26 protein levels were also significantly increased in platelets and plasma from patients with immune thrombotic thrombocytopenic purpura compared with those from unaffected controls. We conclude that ANKRD26 overexpression, resulting from either hereditary or acquired mechanisms, contributes to thrombocytopenia, thrombosis and hematologic malignancies.