A novel ABCA1 variant associated with impaired platelet production contributing to thrombocytopenia in a family with Tangier disease
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 charac...
| Autores: | , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Universidad de Oviedo (UNIOVI) |
| Repositorio: | RUO. Repositorio Institucional de la Universidad de Oviedo |
| Idioma: | inglés |
| OAI Identifier: | oai:dnet:ruo_________::eb59ae1c8592baa11c70b33e436884b7 |
| Acceso en línea: | https://hdl.handle.net/10651/83304 https://dx.doi.org/10.1016/J.JACL.2025.12.009 |
| Access Level: | acceso abierto |
| Palabra clave: | ABCA1 Cholesterol efflux HDL Megakaryopoiesis Platelets Tangier disease Thrombocytopenia |
| Sumario: | 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_005502.4 c.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_005502.4 c.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. |
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