Natural inactivation of a common HLA allele (A*2402) has occurred on at least three separate occasions

Autor: Katharine Magor, Taylor, E. J., Shen, S. Y., Martinez-Naves, E., Valiante, N. M., Wells, R. S., Gumperz, J. E., Adams, E. J., Little, A. -M, Williams, F., Middleton, D., Gao, X., Mccluskey, J., Parham, P., Lienert-Weidenbach, K.
Rok vydání: 1997
Předmět:
Zdroj: Scopus-Elsevier
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.158.11.5242
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: