We describe here the isolation and sequencing of a previously uncharacterized HLA class I gene. This gene, HLA-5.4, is the third non-HLA-A,B,C gene characterized whose sequence shows it encodes an intact class I protein. RNase protection assays with a probe specific for this gene demonstrated its expression in B lymphoblastoid cell lines, in resting T cells, and skin cells, while no mRNA could be detected in the T cell line Molt 4. Consistent with a pattern of expression different from that of other class I genes, DNA sequence comparisons identified potential regulator motifs unique to HLA-5.4 and possibly essential for tissue-specific expression. Protein sequence analysis of human and murine class I antigens has identified 10 highly conserved residues believed to be involved in antigen binding. Five of these are altered in HLA-5.4, and of these, three are nonconservative. In addition, examination of the HLA-5.4 DNA sequence predicts that the cytoplasmic segment of this protein is shorter than that of the classical transplantation antigens. The 3' untranslated region of the HLA-5.4 gene contains one member of a previously undescribed multigene family consisting of at least 30 members. Northern analysis showed that several of these sequences were transcribed, and the most ubiquitous transcript, a 600-nucleotide polyadenylated mRNA, was found in all tissues and cells examined. This sequence is conserved in the mouse genome, where a similar number of copies were found, and one of these sequences was also transcribed, yielding a 600-nucleotide mRNA. The characterization of this unique HLA class I gene and the demonstration of its tissue-specific expression have prompted us to propose that HLA-5.4 be designated HLA-F.

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