A novel splice donor mutation in the thrombopoietin gene leads to exon 2 skipping in a Filipino family with hereditary thrombocythemia.

摘要

In contrast to the familial predisposition observed in somatically acquired myeloproliferative neoplasms (low penetrance, clonal hematopoiesis), the hereditary thrombocythemias (HT) are characterized by Mendelian inheritance, high penetrance, and polyclonal hematopoiesis, and appear to only affect the megakaryocytic lineage. All the molecular alterations identified thus far in patients with HT have involved either THPO (thrombopoietin) or its receptor MPL (myeloproliferative leukemia virus oncogene) genes, with 4 and 3 distinct mutations reported, respectively. The HT-associated THPO mutations were either confirmed or expected to increase the translational efficiency of thrombopoietin without altering the sequence of the mature protein.1 Thrombopoietin, the primary regulator of megakaryopoiesis and platelet production, is produced in the liver, kidney, spleen, and bone marrow.2 Thrombopoietin binds to its receptor and activates the JAK-STAT signaling pathway. The presence of multiple upstream AUG codons (uAUG) within the 5'-untranslated region (5'-UTR) precludes efficient translation and prevents harmful overproduction of this potent cytokine.