title: A point mutation in the EGF-4 domain of β(3) integrin is responsible for the formation of the Sec(a) platelet alloantigen and affects receptor function.
abstract: Neonatal alloimmune thrombocytopenia (NAIT) is caused by fetomaternal platelet incompatibility with maternal antibodies crossing the placenta and destroying fetal platelets. Antibodies against human platelet antigen-1a (HPA-1a) and HPA-5b are responsible for the majority of NAIT cases. We observed a suspected NAIT in a newborn with a platelet count of 25 G/l and petechial haemorrhages. Serological analysis of maternal serum revealed an immunisation against αIIbβ3 on paternal platelets only, indicating the presence of an antibody against a new rare alloantigen (Sec(a)) residing on αIIbβ3. The location of Sec(a) on αIIbβ3 was confirmed by immunoprecipitation. Nucleotide sequence analysis of paternal β3 revealed a single nucleotide exchange (G(1818)T) in exon 11 of the β3 gene (ITGB3), changing Lys(580) (wild-type) to Asn(580) (Sec(a)). Two additional members of the family Sec were typed Sec(a) positive, but none of 300 blood donors. Chinese hamster ovary cells expressing Asn(580), but not Lys(580) αIIbβ3, bound anti-Sec(a), which was corroborated by immunoprecipitation. Adhesion of transfected cells onto immobilised fibrinogen showed reduced binding of the Asn(580) variant compared to wild-type αIIbβ3. Analysis of transfected cells with anti-LIBS and PAC-1 antibody showed reduced binding when compared to the wild-type. No such effects were observed with Sec(a) positive platelets, which, however, are heterozygous for the Lys(580)Asn mutation. In this study, we describe a NAIT case caused by maternal alloimmunisation against a new antigen on αIIbβ3. Analysis with mutant transfected cells showed that the Lys(580)Asn mutation responsible for the formation of the Sec(a) antigenic determinant affects αIIbβ3 receptor function.
authors: Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Langhansstr. 7, D-35385 Giessen, Germany.
authors: Ulrich J
authors: UJ
authors: Sachs
authors: Tamam
authors: T
authors: Bakchoul
authors: Olga
authors: O
authors: Eva
authors: Astrid
authors: A
authors: Giptner
authors: Gregor
authors: G
authors: Bein
authors: Richard H
authors: RH
authors: Aster
authors: Maria
authors: M
authors: Gitter
authors: Julie
authors: J
authors: Peterson
authors: Sentot
authors: S
authors: Santoso
mesh_terms: D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D018821:CD18 Antigens / Q000737:chemistry*; D016466:CHO Cells; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000737:chemistry*; D005260:Female; D005333:Fetus / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry; D005838:Genotype; D006470:Hemorrhage / Q000097:blood; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D039661:Integrin beta3 / Q000737:chemistry*; D007518:Isoantibodies / Q000737:chemistry; D007519:Isoantigens / Q000737:chemistry*; D010973:Platelet Adhesiveness; D040201:Platelet Membrane Glycoprotein IIb / Q000737:chemistry; D017354:Point Mutation; D011247:Pregnancy; D011248:Pregnancy Complications; D017422:Sequence Analysis, DNA; D014162:Transfection
chemical_list: D018821:CD18 Antigens; D039661:Integrin beta3; D007518:Isoantibodies; D007519:Isoantigens; D040201:Platelet Membrane Glycoprotein IIb; D004815:Epidermal Growth Factor; D005340:Fibrinogen