THPO – Familial Thrombocytosis

Hereditary thrombocythemia is a rare autosomal dominant disorder characterized by persistent thrombocytosis ([HP:0001894]) and susceptibility to thrombotic events. THPO encodes thrombopoietin, the principal hematopoietic cytokine driving megakaryocyte proliferation and platelet production ([Gene Symbol]). Germline gain-of-function variants in THPO underlie familial thrombocytosis (MONDO:0019111).

In four unrelated pedigrees, heterozygous THPO mutations segregate with thrombocytosis in >20 affected individuals. A G→T transversion in the 5′ UTR (c.-31G>T) co-segregated in 4 members of a British kindred (PMID:19553636). In a Dutch family with 11 affected relatives, a splice-donor mutation c.13+1G>C demonstrated a LOD score of 3.5 (PMID:9425899). A Japanese pedigree harbors a c.13+1G>A variant in multiple affected subjects (PMID:37962621). These data confirm autosomal-dominant inheritance with consistent segregation.

The variant spectrum comprises UTR point mutations (c.-47delG; c.-31G>T), splice-donor alterations (c.13+1G>C; c.13+1G>A; c.13+2T>C; c.13+5G>A), and small indels, each identified in independent families (PMID:38548144).

Functional assays in reticulocyte lysates and cell-based expression systems show that UTR mutations disrupt upstream open reading frames, enhancing translational efficiency, while splice-site mutations induce exon 3 skipping and loss of a suppressive uORF, leading to 2- to 8-fold increased TPO secretion (PMID:9425899; PMID:37962621; PMID:38548144).

A minority of familial thrombocytosis cases lack THPO or MPL lesions, indicating genetic heterogeneity (PMID:16995886). No studies have refuted the THPO association in mutation-positive families.

Integration of segregation and functional data supports a strong role for THPO gain-of-function mutations in autosomal-dominant familial thrombocytosis. These findings enable targeted genetic testing, inform prognosis, and guide therapeutic strategies.

Key Take-home: Gain-of-function THPO variants are a robust cause of familial thrombocytosis, facilitating precision diagnosis and management.

References

• Blood • 2009 • Association of hereditary thrombocythemia and distal limb defects with a thrombopoietin gene mutation. PMID:19553636
• Nature Genetics • 1998 • An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. PMID:9425899
• Annals of Hematology • 2024 • Hereditary thrombocythemia due to splicing donor site mutation of THPO in a Japanese family. PMID:37962621
• Experimental Hematology • 2024 • Relative impact of THPO mutation causing hereditary thrombocythemia. PMID:38548144
• British Journal of Haematology • 2006 • A family with hereditary thrombocythaemia and normal genes for thrombopoietin and c-Mpl. PMID:16995886

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