title: A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome.
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.
authors.affiliation: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, United Kingdom. christiane.albrecht@wzw.tum.de
authors.forename: Christiane
authors.initials: C
authors.lastname: Albrecht
authors.forename: John H
authors.initials: JH
authors.lastname: McVey
authors.forename: James I
authors.initials: JI
authors.lastname: Elliott
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sardini
authors.forename: Ildiko
authors.initials: I
authors.lastname: Kasza
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mumford
authors.forename: Rossi P
authors.initials: RP
authors.lastname: Naoumova
authors.forename: Edward G D
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: Katalin
authors.initials: K
authors.lastname: Szabo
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Higgins
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001693:Biological Transport, Active / Q000187:drug effects; D025861:Blood Coagulation Disorders, Inherited / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002460:Cell Line; D004247:DNA / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005816:Genetic Complementation Test; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010718:Phosphatidylserines / Q000097:blood / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D010718:Phosphatidylserines; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D004247:DNA; D002118:Calcium