Loss of function mutations of the the ATP-binding cassette-1 (ABCA1) gene are the cause of Tangier disease (TD) in homozygous subjects and familial HDL deficiency (FHD) in heterozygous subjects. These disorders are characterized by reduced plasma HDL-cholesterol and altered efflux of cholesterol from cells. Previous studies in TD patients and ABCA1(-/-) murine models reported defects in platelet count, morphology and function, but the issue is still controversial. We analysed three subjects with low to very low HDL cholesterol levels due to loss of function mutations of the ABCA1 gene. Two related patients with FHD were heterozygous carriers of two mutations on the same ABCA1 allele; one, with TD, was homozygous for a different mutation. Mild to moderate thrombocytopenia was observed in all patients. No morphological platelet abnormalities were detected under optical or electron microscopy. History of moderate bleeding tendency was recorded only in one of the FHD patients. Only limited alterations in platelet aggregation and activation of the integrin αIIbβ3 were observed in one FHD patient. While α-granule secretion (P-selectin), content and secretion of platelet δ-granules (serotonin, ATP, and ADP) and thromboxane B2 synthesis were normal in all patients, the expression of lysosomal CD63, in response to some agonists, was reduced in the TD patient. In conclusion, three patients carrying ABCA1 genetic variants had low platelet count, with the lowest values observed in TD, not associated with major alterations in platelet morphology and response to agonists, nor bleeding.

Reduced platelet count, but no major platelet function abnormalities, are associated with loss of function ATP-binding cassette-1 (ABCA1) gene mutations

MINUZ, Pietro;MENEGUZZI, Alessandra;FAVA, Cristiano;CALABRIA, Stefano;BENATI, Donatella;POLI, GIOVANNI;ZANCANARO, Carlo;
2017-01-01

Abstract

Loss of function mutations of the the ATP-binding cassette-1 (ABCA1) gene are the cause of Tangier disease (TD) in homozygous subjects and familial HDL deficiency (FHD) in heterozygous subjects. These disorders are characterized by reduced plasma HDL-cholesterol and altered efflux of cholesterol from cells. Previous studies in TD patients and ABCA1(-/-) murine models reported defects in platelet count, morphology and function, but the issue is still controversial. We analysed three subjects with low to very low HDL cholesterol levels due to loss of function mutations of the ABCA1 gene. Two related patients with FHD were heterozygous carriers of two mutations on the same ABCA1 allele; one, with TD, was homozygous for a different mutation. Mild to moderate thrombocytopenia was observed in all patients. No morphological platelet abnormalities were detected under optical or electron microscopy. History of moderate bleeding tendency was recorded only in one of the FHD patients. Only limited alterations in platelet aggregation and activation of the integrin αIIbβ3 were observed in one FHD patient. While α-granule secretion (P-selectin), content and secretion of platelet δ-granules (serotonin, ATP, and ADP) and thromboxane B2 synthesis were normal in all patients, the expression of lysosomal CD63, in response to some agonists, was reduced in the TD patient. In conclusion, three patients carrying ABCA1 genetic variants had low platelet count, with the lowest values observed in TD, not associated with major alterations in platelet morphology and response to agonists, nor bleeding.
2017
ATP-binding cassette-1; Tangier disease; bleeding; familial HDL deficiency; platelet function; thrombocytopenia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/967650
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