Structural definition of the A(*)74 group: Implications for matching in bone marrow transplantation with alternative donors

Abstract

We have identified two new A(*)74 alleles (A(*)7402 and 7403) in two unrelated individuals. A(*)7402 differs from A(*)7401 by a single amino acid substitution in the signal peptide and may be the result of a gene conversion event at the 3' end of exon 1. A(*)7403 differs from A(*)7401 by a single amino acid exchange in the α1 domain and is most likely due to a point mutation in exon 2, since no HLA class I donor allele has been found. Since A(*)7402 appears to be the ancestor of the other two A(*)74 alleles, it is possible that A(*)7401 and 7403 have been created by successive point mutations. The sequences of the expressed proteins of A(*)7401 and 7402 are identical. The heavy chain sequence of A(*)7403 differs from these alleles at the crucial residue 79 which is located in the sequence stretch of the α1 α-Helix where the Bw4/Bw6 determinants have been identified and which probably affects TCR interaction. This variation can therefore be expected to stimulate alloreactive T cells, graft rejection and graft versus host disease emphasizing the relevance for matching in bone marrow transplantation with alternative donors.