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A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome

Albrecht, C; McVey, JH; Elliott, JI; Sardini, A; Kasza, I; Mumford, AD; Naoumova, RP; Tuddenham, EGD; Szabo, K; Higgins, CF

Authors

C Albrecht

JH McVey

JI Elliott

A Sardini

I Kasza

AD Mumford

RP Naoumova

EGD Tuddenham

K Szabo

CF Higgins



Abstract

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.

Citation

Albrecht, C., McVey, J., Elliott, J., Sardini, A., Kasza, I., Mumford, A., …Higgins, C. (2005). A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome. Blood, 106(2), 542-549. https://doi.org/10.1182/blood-2004-05-2056

Journal Article Type Article
Publication Date Jul 1, 2005
Deposit Date May 15, 2007
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Not Peer Reviewed
Volume 106
Issue 2
Pages 542-549
DOI https://doi.org/10.1182/blood-2004-05-2056