A functional platelet fibrinogen receptor with a deletion in the cysteine-rich repeat region of the beta(3) integrin: the Oe(a) alloantigen in neonatal alloimmune thrombocytopenia

This report describes a new low-frequency alloantigen, Oe(a), responsible for a case of neonatal alloimmune thrombocytopenia (NAIT). In a population study none of 600 unrelated blood donors was an Oe(a) carrier. By immunochemical studies the Oe(a) antigen could be assigned to platelet glycoprotein (...

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Bibliographic Details
Published in:	Blood 2002-02, Vol.99 (4), p.1205
Main Authors:	Santoso, Sentot, Kiefel, Volker, Richter, Ina G, Sachs, Ulrich J H, Rahman, Abdul, Carl, Bettina, Kroll, Harmut
Format:	Article
Language:	eng
Subjects:	Adult Antigens, CD - genetics Antigens, CD - immunology Antigens, CD - physiology Antigens, Human Platelet - genetics Antigens, Human Platelet - immunology Antigens, Human Platelet - physiology Cysteine DNA Mutational Analysis Female Genetic Variation - genetics Genetic Variation - immunology Humans Infant, Newborn Integrin beta3 Isoantibodies - adverse effects Isoantibodies - immunology Isoantigens - genetics Isoantigens - immunology Male Maternal-Fetal Exchange - immunology Pedigree Platelet Glycoprotein GPIIb-IIIa Complex - genetics Platelet Glycoprotein GPIIb-IIIa Complex - immunology Platelet Glycoprotein GPIIb-IIIa Complex - physiology Platelet Membrane Glycoproteins - genetics Platelet Membrane Glycoproteins - immunology Platelet Membrane Glycoproteins - physiology Pregnancy Pregnancy Complications, Hematologic - etiology Pregnancy Complications, Hematologic - immunology Repetitive Sequences, Amino Acid Sequence Deletion Thrombocytopenia - etiology Thrombocytopenia - genetics Thrombocytopenia - immunology
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Summary:	This report describes a new low-frequency alloantigen, Oe(a), responsible for a case of neonatal alloimmune thrombocytopenia (NAIT). In a population study none of 600 unrelated blood donors was an Oe(a) carrier. By immunochemical studies the Oe(a) antigen could be assigned to platelet glycoprotein (GP) IIIa. Sequencing of GPIIIa complementary DNA from an Oe(a) (+) individual showed deletion of a lysine residue at position 611 (DeltaLys(611)). Analysis of 20 Oe(a) (-) and 3 Oe(a) (+) individuals showed that the DeltaLys(611) form of GPIIIa was related to the phenotype. Anti-Oe(a) reacted with the DeltaLys(611), but not with the wild-type isoforms on stable transfectants expressing GPIIIa, indicating that DeltaLys(611) directly induces the expression of Oe(a) epitopes. Under nonreducing conditions the Pro(33)DeltaLys(611) variant migrated with a slightly decreased molecular weight compared to the Pro(33)Lys(611) isoform suggesting that DeltaLys(611) has an influence on the disulfide bonds of GPIIIa. The Pro(33)DeltaLys(611) GPIIIa could undergo conformational changes and bind to fibrinogen in a similar manner as the Pro(33)Lys(611) isoform. No difference was found in the tyrosine phosphorylation of pp125(FAK), suggesting that DeltaLys(611) has no effect on integrin function. In contrast to all other low-frequency antigens, the DeltaLys(611) isoform was associated with the HPA-1b, but not with the high frequency HPA-1a allele. Comparison with GPIIIa DNA from nonhuman primates indicated that the HPA-1a allele represents the ancestral form of GPIIIa. It can be assumed that the Oe(a) form did arise as a result of a mutational event from an already mutated GPIIIa allele.
ISSN:	0006-4971 1528-0020