THPO – Congenital Amegakaryocytic Thrombocytopenia

THPO encodes thrombopoietin, a key regulator of megakaryocyte differentiation and platelet production. Pathogenic variants in THPO have been implicated in Congenital Amegakaryocytic Thrombocytopenia, a rare autosomal recessive bone marrow failure syndrome characterized by neonatal thrombocytopenia and absent megakaryocytes.

Genetic evidence supports a strong autosomal recessive inheritance with five probands across three families. A consanguineous Saudi child was homozygous for a deletion spanning exon 6 and presented with unexplained thrombocytopenia at age seven (PMID:39479124). In a separate pedigree, three siblings carried a homozygous c.355C>T (p.Arg119Cys) variant with early-onset thrombocytopenia evolving into marrow aplasia (PMID:29191945). A fourth unrelated patient harbored a homozygous promoter mutation c.-323C>T that impaired THPO transcription (PMID:36226497).

Segregation analysis demonstrated three additional affected siblings with co-segregation of p.Arg119Cys and no disease in heterozygotes, confirming autosomal recessive transmission. The variant spectrum spans missense changes in the receptor-binding domain and noncoding promoter alterations, with recurrent p.Arg119Cys in consanguineous cohorts.

Functional assays confirm loss-of-function as the mechanism: p.Arg119Cys reduces secretion of thrombopoietin and impairs MPL receptor activation, consistent with low serum hormone levels in patients (PMID:29191945). The c.-323C>T promoter substitution abolishes ETS1 and STAT4 binding, leading to deficient THPO transcription and production (PMID:36226497).

Therapeutically, THPO-deficient CAMT patients respond robustly to THPO-mimetic agents: romiplostim induced sustained trilineage hematopoiesis and transfusion independence in p.Arg119Cys cases, while eltrombopag elevated platelet counts in promoter-mutant CAMT (PMID:29191945; PMID:36226497). Early molecular diagnosis thus directs targeted therapy and may obviate invasive procedures.

No conflicting evidence has been reported. Integrating genetic and experimental findings yields a strong gene–disease association. Key take-home: genetic screening for THPO variants is critical in neonatal thrombocytopenia to enable prompt THPO-mimetic treatment and improve clinical outcomes.

References

• Cureus • 2024 • A Rare THPO Gene Mutation in a Saudi Female Child: A Case Report and Literature Review PMID:39479124
• EMBO molecular medicine • 2018 • Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim PMID:29191945
• Haematologica • 2023 • Defective binding of ETS1 and STAT4 due to a mutation in the promoter region of THPO as a novel mechanism of congenital amegakaryocytic thrombocytopenia PMID:36226497

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