THPO

Chr 3ARAD

thrombopoietin

Also known as: CAMT2, MGDF, MKCSF, ML, MPLLG, THC9, THCYT1, TPO

NCBI Gene: 7066 ENSG00000090534 UniProt: P40225 OMIM: 600044

Megakaryocytopoiesis is the cellular development process that leads to platelet production. The main functional protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene. Mutations in this gene are the cause of thrombocythemia 1. Alternative promoter usage and differential splicing result in multiple transcript variants differing in the 5' UTR and/or coding region. Multiple AUG codons upstream of the main open reading frame (ORF) have been identified, and these upstream AUGs inhibit translation of the main ORF at different extent. [provided by RefSeq, Feb 2014]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.703 OMIM phenotypes

Clinical Summary— THPO

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Gene-Disease Validity (ClinGen)

congenital amegakaryocytic thrombocytopenia · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.197

Z-score 2.24

OE 0.27 (0.12–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.41Z-score

OE missense 0.92 (0.81–1.04)

171 obs / 186.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.12–0.70)

0≤0.351.4

Missense OE?0.92 (0.81–1.04)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 3 / 11.1Missense obs/exp: 171 / 186.8Syn Z: -2.11

This gene — mechanism propensity

0.6647th %ile

GOF

0.73top 25%

LOF

0.3259th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFIn order to investigate whether somatic THPO gene mutations play a role in sporadic pediatric myeloproliferative diseases, we performed a mutation screening of a large representative cohort of pediatric acute myeloid leukemia, myeloid leukemia of Down syndrome, and juvenile myelomonocytic leukemia s1

LOFConsistent with two of three previously described patients, our patient also presents with thrombocytopenia, which we postulate is caused by haploinsufficiency of THPO.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References