Familial Essential Thrombocythemia Associated With One-Base Deletion in the 5′-Untranslated Region of theThrombopoietin Gene

Abstract

Familial essential thrombocythemia (ET) is inherited in an autosomal-dominant manner. This finding implies that familial ET may arise as a consequence of a mutation(s) that activates platelet production. In 1994, the thrombopoietin (TPO) gene was isolated and cloned. The TPO-TPO receptor, encoded for by thec-mpl gene, are essential regulators of thrombopoiesis. Alterations of TPO or c-Mpl thus may constitute a pathogenic event leading to familial ET. In a case of familial ET presented in our institute, serum TPO levels were significantly elevated in affected members of the family as compared with nonaffected members. Moreover, we identified a one-base deletion in the 5′-untranslated region of theTPO gene in affected but not in nonaffected family members. In vitro experiments showed that the identified mutation increased TPO production. Based on our findings, we propose that this region of theTPO gene may play a crucial role in regulating TPO expression. Our results strongly suggest that the identified mutation leads to familial ET. © 1998 by The American Society of Hematology.

An additional family with association of hereditary thrombocytosis and transverse limb deficiency: Confirmation of a rare clinical spectrum

“…1 bottom). The identical mutation has previously been observed in a family with autosomal dominant thrombocythemia [Kondo et al, 1998], where five affected patients are reported to have platelet excess. Skeletal defects have not been reported in that family.…”

Thrombopoietin from beginning to end

“…Several distinct mutations of the THPO gene have been identified in patients with congenital thrombocythaemia (Jorgensen et al , ; Kondo et al , ; Wiestner et al , ; Ghilardi & Skoda, ). While distinct, each of the mutations thus far described result in greatly enhanced efficiency of translation of THPO mRNA, increasing TPO levels and hence, causing thrombocytosis.…”

“…Only if the 7th ATG is skipped does a ribosome translate TPO from the 8th ATG. All of the described THPO mutants that cause thrombocythaemia do so by improving translation efficiency, either by converting an upstream ATG (ATG 5 or ATG7) into the THPO initiating start codon (by mutation‐induced alternate splicing or by a frame shifting deletion), or by creation of a premature stop codon in open reading frame 7, allowing ribosomal re‐initiation at ATG8 (Jorgensen et al , ; Kondo et al , ; Wiestner et al , ; Ghilardi et al , ; Cazzola & Skoda, ).…”

Advances in understanding the pathogenesis of familial thrombocythaemia

“…The second mutation was discovered in five members of a Japanese family in 1998 (Kondo et al , 1998). This mutation involves the deletion of a guanine located 47 bases upstream of the physiological initiation AUG codon.…”

“…Subjects with hereditary thrombocytosis were mostly referred to haematologists for suspected MPN and– whenever investigated – the bone marrow histology was seemingly indistinguishable from that typical for ET. Nevertheless, in contrast to patients with ET, who have frequent vascular complications and possible evolution in fibrosis or acute leukaemia, patients with hereditary forms due to THPO mutations were regarded as asymptomatic (Kikuchi et al , 1995; Jorgensen et al , 1998; Kondo et al , 1998) and vascular complications were not reported in family members carrying the MPL ‐S505N mutation (Ding et al , 2004). As a result, the notion that hereditary thrombocytosis are benign diseases became widely accepted, having a vascular risk significantly lower than ET and rarely associated with mild splenomegaly (Dror & Blanchette, 1999; Skoda & Prchal, 2005).…”