Hereditary thrombocythaemia in a Japanese family is caused by a novel point mutation in the thrombopoietin gene

Abstract

Summary. 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 identi®ed 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 H -untranslated region (5 H -UTR) of the TPO mRNA and when assayed in reticulocyte lysates, improved translational ef®ciency 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.

3q26.33–3q27.2 microdeletion: A new microdeletion syndrome?

“…Gain of function mutations in this gene have been shown to be responsible for hereditary thrombocythaemia [8,9]. CLCN2, a gene for which the mice knock-out model of its homolog demonstrates leukoencephalopathy [10] and degeneration of retinal and testicular cells, leading to male infertility is present in the deleted region [11].…”

An 8.4‐Mb 3q26.33‐3q28 microdeletion in a patient with blepharophimosis–intellectual disability syndrome and a review of the literature

“…Indeed, at least half of the 3q26.33‐3q27.2 microdeletion cases have thrombocytopenia (Table 1), and mutations in THPO gene causing improved translational efficiency have been shown to be responsible for hereditary autosomal‐dominant thrombocythemia 17, 18. However, LAMP3 gene is not located in the SRO and therefore, is probably not causative for the common phenotype as was suggested before.…”

Clinical utility gene card for: Hereditary thrombocythemia

“…4,5 G516T of the 5 0 -untranslated region. 6,7 Mutations of THPO signallingassociated factors other than MPL and JAK2 (eg, SH2B adaptor protein 3/SH2B3) have not yet been reported in hereditary cases.…”

“…Hereditary thrombocythemia cases with associated THPO alterations (THCYT1) have been described in Japan, 4,6,7 Italy, 5 the Netherlands 1,2 and Poland. 3 In an affected Italian family with THPO 1-BP DEL, 3252G distal unilateral limb defects were present; presumably secondary defects (grandfather without limb defects; father with absence of right forearm and hand and absence of right foot, one of three male children with absence of the right foot, the calcaneus and astragalus; a second child with absence of the last phalange of 2nd digit and last 2 phalanges of 3rd to 5th digits; the third child had no limb defects).…”