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Blood, 15 July 2005, Vol. 106, No. 2, pp. 542-549.
Prepublished online as a Blood First Edition Paper on March 24, 2005; DOI 10.1182/blood-2004-05-2056.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome
Christiane Albrecht,
John H. McVey,
James I. Elliott,
Alessandro Sardini,
Ildiko Kasza,
Andrew D. Mumford,
Rossi P. Naoumova,
Edward G. D. Tuddenham,
Katalin Szabo, and
Christopher F. Higgins
From the Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, United Kingdom; National Medical Center, Institute of Haematology and Immunology, Research Group of the Hungarian Academy of Sciences, Budapest, Hungary; Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary; and Physiology Weihenstephan, Technical University Münich, Freising, Germany.
Scott syndrome (SS) is a bleeding disorder characterized by a failure to expose phosphatidylserine (PS) to the outer leaflet of the platelet plasma membrane. Because the adenosine triphosphate (ATP)–binding cassette transporter A1 (ABCA1) is implicated in the exofacial translocation of PS, we assessed its role in the pathophysiology of a patient with SS. Substantially reduced levels of ABCA1 mRNA were found in the patient's leukocytes, compared with controls. The SS patient was heterozygous for a novel missense mutation c.6064G>A (ABCA1 R1925Q), absent from unaffected family members and controls. Both mutant and wild-type alleles were reduced in mRNA expression, and no causative mutation for this phenomenon was identified in the ABCA1 gene or its proximal promoter, suggesting a putative second mutation in a trans-acting regulatory gene may also be involved in the disorder in this patient. In vitro expression studies showed impaired trafficking of ABCA1 R1925Q to the plasma membrane. Overexpression of wild-type ABCA1 in SS lymphocytes complemented the Ca2+-dependent PS exposure at the cell surface. These data identify a mutation in ABCA1 that contributes to the defective PS translocation phenotype in our patient with SS.
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