Tuesday, 7 July 2026

Gómez-Coronado D, Rodríguez-Jiménez C, Villar P, Fernández-Suárez ME, Eble JA, de la Peña G, Martínez-Botas J, Acebes-Huerta A, Prieto-Cazorla P, Villa-Fajardo M, Lasunción MA, Rodríguez-Nóvoa S, Gutiérrez L. A novel ABCA1 variant associated with impaired platelet production contributing to thrombocytopenia in a family with Tangier disease

J. Clin. Lipidol. 2026

"ABCA1 dysfunction alters megakaryocyte maturation in Tangier disease". - Dr. Diego Gómez-Coronado Cáceres

Summary:

Background: ATP-binding cassette A1 (ABCA1) is a membrane-associated cholesterol efflux pump that is crucial for high-density lipoprotein (HDL) biogenesis and cellular cholesterol homeostasis. Pathogenic variants in the ABCA1 gene cause Tangier disease (TD), a rare autosomal recessive disorder characterized by nearly absent HDL in plasma and cholesteryl ester accumulation in tissue macrophages. Clinical manifestations vary among patients with TD, including splenomegaly, thrombocytopenia, and cardiovascular disease (CVD), with no clear association with specific ABCA1 pathogenic variants. Thrombocytopenia is attributed to hypersplenism-mediated platelet clearance; however, there is controversy regarding platelet production and function in TD.

Objective: To identify and functionally characterize the suspected alteration in ABCA1, and to study platelet production and function in a Spanish family with HDL deficiency and thrombocytopenia.

Methods: Lipid and apolipoprotein profile analyses, next-generation/Sanger sequencing, in vitro ABCA1 expression and cholesterol efflux assays, primary megakaryocyte differentiation cultures, and platelet functional studies were performed.

Results: We identified a novel variant, ABCA1:NM_005502.4c.3306del:p.(Ile1103Serfs*16), which results in a truncated protein with defective apolipoprotein AI-dependent cholesterol efflux. Mild to severe thrombocytopenia and splenomegaly were observed in homozygous carriers; however, there was no clinical history of CVD. Platelet degranulation was overtly normal, although a distinct aggregation profile was observed in ABCA1:p.(Ile1103Serfs*16) carriers. Impaired megakaryocyte differentiation associated with aberrant accumulation of neutral lipids in megakaryocytes was observed in primary cell cultures from homozygous carriers.

Conclusion: The ABCA1:NM_005502.4c.3306del:p.(Ile1103Serfs*16) variant causes TD. Our findings suggest that thrombocytopenia in TD is not merely due to platelet clearance but also a consequence of ineffective megakaryopoiesis due to ABCA1 dysfunction.

Why do you highligth this publication?

Despite their severe deficiency of HDL, a large proportion of patients with Tangier disease (TD) do not suffer from cardiovascular disease, as was the case with the family studied herein. The reason behind this striking feature is not well known. TD is frequenly associated with splenomegaly and thrombocytopenia, which are uncommon in other HDL deficiency syndromes. Thrombocytopenia in TD is attributed to hypersplenism-mediated enhanced platelet clearance. However, there has been very little research into how the defective ABCA1 cholesterol transporter, which causes TD, affects platelet production and function. Our findings suggest that the novel ABCA1 variant that we have described disrupts platelet production in vitro by impairing megakaryocyte maturation, but has a rather moderate effect on platelet function.