Molecular analysis of the York antigen of the Knops blood group system
Barbera Veldhuisen1, Peter C Ligthart, Gestur Vidarsson
1Department of Experimental Immunohematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. b.veldhuisen@sanquin.nl
Insights
The York (Yk(a)) antigen absence is linked to a CR1 gene mutation in Exon 26. This discovery completes the known Knops blood group antigen polymorphisms, enabling molecular typing for blood transfusion compatibility.
Area of Science:
- Genetics
- Immunology
- Hematology
Background:
- Knops blood group antigens are located on complement component (3b/4b) receptor 1 (CR1/CD35).
- Most known Knops antigens are associated with CR1 gene polymorphisms in Exon 29.
- The molecular basis for the York (Yk(a)) antigen has remained undescribed.
Purpose of the Study:
- To identify the specific CR1 gene polymorphism responsible for the absence of the Yk(a) antigen.
- To enable molecular typing for the Yk(a) blood group antigen.
Main Methods:
- Serologic typing identified Yk(a)-negative individuals.
- Partial sequencing of the CR1 gene was performed and compared between Yk(a)-positive and negative individuals.
- The functional impact of the identified mutation was assessed by expressing CR1 domains in HEK293 cells.
Main Results:
- A 4223C>T mutation in Exon 26 of the CR1 gene was identified as the cause of Yk(a) antigen absence.
- This mutation leads to a 1408T>M amino acid change.
- Expression studies confirmed that the mutation abolishes Yk(a) antigen expression on cells.
Conclusions:
- A specific CR1 gene sequence variation (4223C>T) is definitively linked to the absence of the Yk(a) antigen.
- All known Knops blood group antigen polymorphisms are now molecularly characterized.
- This finding facilitates molecular testing for improved red blood cell alloantibody identification.
Background:
Antigens of the Knops blood group system are present on complement component (3b/4b) receptor 1 (CR1/CD35), which is a transmembrane glycoprotein encoded by the CR1 gene. Eight of the nine known antigens of this system are linked to polymorphisms in Exon 29. The molecular background of one antigen, York (Yk(a)), has not yet been described.
Study Design And Methods:
We aimed to identify a polymorphism associated with the absence of Yk(a) to enable molecular typing. Yk(a)-negative individuals were identified by serologic typing. Their CR1 gene was partially sequenced and compared to that of Yk(a)-positive individuals. Loss of Yk(a) antigen was investigated by expressing the SCR22/23 domain of both wild-type and mutated CR1 as a GPI-linked protein on HEK293 cells.
Results:
We observed that absence of the Yk(a) antigen is caused by a mutation in Exon 26 of the CR1 gene. This 4223C>T mutation results in a 1408T>M change at the protein level. Ten of 117 donors (8.5%) were homozygous TT, confirming the Caucasian frequency of 8% Yk(a)-negative individuals. Serologically, these TT donors showed a Yk(a)-negative phenotype, while CC/CT individuals were Yk(a)-positive. While the Yk(a) antigen was present on HEK293 cells expressing wild-type constructs, cells expressing the 4223C>T variant were Yk(a) negative.
Conclusion:
We identified a 4223C>T sequence variation in the CR1 gene causing absence of the Yk(a) antigen of the Knops blood group system. With this finding, all polymorphisms of the known Knops blood group antigens have been revealed, enabling molecular testing to contribute to red blood cell alloantibody identification procedures.
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