Natural inactivation of a common HLA allele (A2402) has occurred on at least three separate occasions

• Published in: The Journal of immunology (1950) Vol. 158; no. 11; pp. 5242 - 5250
• Main Authors: Magor, KE, Taylor, EJ, Shen, SY, Martinez-Naves, E, Valiante, NM, Wells, RS, Gumperz, JE, Adams, EJ, Little, AM, Williams, F, Middleton, D, Gao, X, McCluskey, J, Parham, P, Lienert-Weidenbach, K
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-06-1997
• Subjects: Alleles; B-Lymphocytes - immunology; Cell Line; DNA, Complementary - genetics; DNA, Complementary - isolation & purification; Gene Expression Regulation - immunology; Genome, Human; HLA Antigens - genetics; HLA Antigens - immunology; Humans; RNA, Messenger - analysis; RNA, Messenger - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.158.11.5242

HLA-A*2402 is common and widely distributed in human populations. Several individuals were identified who type genotypically for A*2402, but are serologically null for the HLA-A24 Ag. Sequencing and transfection of genomic DNA fragments containing null and wild-type A*2402 alleles, and the related A*2301 allele, revealed three different null alleles (A*2409N, A*2411N, and A*2402(low)), each of which differs from A*2402 by a single nucleotide change within the 6.7-kb sequence. The A*2301 and A*2402 sequences differ by no substitutions additional to those previously determined for the 1.1-kb cDNA. In exon 4, A*2409N has an in-frame stop codon, while A*2411N has a nucleotide insertion that alters the reading frame, causing premature termination. A*2402(low) has a nucleotide substitution near the splice acceptor site for intron 2 that impairs the production of correctly spliced mRNA. For A*2409N and A*2411N, mRNA is undetectable by Northern analysis, whereas A*2402(low) produces a low level of mRNA and a concomitant amount of normal A*2402 protein at the cell surface. The protein expressed from the A*2402(low) allele is sufficient to stimulate an alloreactive T cell response. On a background of unexpected sequence homogeneity, the single nucleotide changes in the A*2409N, A*2411, and A*2402(low) alleles have dramatic effects upon gene expression and are of likely importance for HLA matching in clinical transplantation. Segregation of at least three independently inactivated A*2402 alleles in human populations raises the possibility that loss of A*2402 may be the result of natural selection.