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Thrombopoietin (THPO) is an essential factor for platelet production. Hereditary thrombocythemia (HT) is caused by a germline mutation of THPO, MPL, or JAK2 and is inherited in an autosomal-dominant manner. We identified a Japanese family with HT due to a point mutation of the splicing donor site of the THPO gene (THPO c.13 + 1G > A). Bone marrow biopsy showed increased megakaryocytes mimicking essential thrombocythemia. One affected family member developed chronic myeloid leukemia. We cloned the mutation and developed mutated and wild type THPO expression vectors. Molecular analysis showed that the mutation causes an exon 3 skipping transcript of THPO that abrogates a suppressive untranslated upstream open reading frame. Although the transcript levels of THPO mRNA were comparable, mutated transcripts were more efficiently translated and THPO protein expression was significantly higher than that of the wild type., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A 83-year-old female patient was admitted to our hospital due to hematological manifestation of juvenile granulocytes and macrocytic anemia. Bone marrow (BM) examination revealed erythroid dysplasia and cytoplasmic blasts, and hence the patient was diagnosed with myelodysplastic syndrome with ring sideroblasts and with single lineage dysplasia (MDS-RS-SLD). Erythrocyte transfusion was performed as a supportive therapy, and there was a gradual increase in the number of blood cells. Therefore, BM re-examination was performed and it was confirmed that the number of megakaryocytes increased, so the patient's condition was determined as myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN with RS-T). Incidentally, gene mutation analysis showed CALR gene mutation. Thereafter, administration of hydroxycarbamide and anagrelide did not show adverse events and complications, and a good blood count control was obtained. Furthermore, it was also confirmed that an SF3B1 gene mutation is highly positive in MDS-RS. There was no report on CALR-mutant MDS/MPN in Japan, and it is a rare disease overseas.

Hereditary thrombocythaemia (HT) with clinical features very similar to essential thrombocythaemia (ET) has been found to be transmitted as an autosomal dominant trait in several families. Here we studied the pathogenesis of HT in a previously described Japanese kindred. We found markedly elevated thrombopoietin (TPO) serum levels in all affected individuals and identified a novel point mutation in the TPO gene, a G --> T transversion at position 516 of the TPO mRNA (G516T) that co-segregated with the HT phenotype in all affected family members. This mutation is located in the 5'-untranslated region (5'-UTR) of the TPO mRNA and when assayed in reticulocyte lysates, improved translational efficiency of in vitro transcribed TPO mRNA. Cell lines transfected with the mutant TPO cDNA secreted up to 8-fold more TPO protein than cells transfected with the normal cDNA. We provide a molecular model of how the mutation partially disables the physiologic repression of TPO translation and thereby causes thrombocytosis. This is the third family in which HT has been caused by the loss of translational inhibition of TPO mRNA.