title: Natural inactivation of a common HLA allele (A*2402) has occurred on at least three separate occasions.
abstract: 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.
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, CA 94305, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Magor
authors.forename: E J
authors.initials: EJ
authors.lastname: Taylor
authors.forename: S Y
authors.initials: SY
authors.lastname: Shen
authors.forename: E
authors.initials: E
authors.lastname: Martinez-Naves
authors.forename: N M
authors.initials: NM
authors.lastname: Valiante
authors.forename: R S
authors.initials: RS
authors.lastname: Wells
authors.forename: J E
authors.initials: JE
authors.lastname: Gumperz
authors.forename: E J
authors.initials: EJ
authors.lastname: Adams
authors.forename: A M
authors.initials: AM
authors.lastname: Little
authors.forename: F
authors.initials: F
authors.lastname: Williams
authors.forename: D
authors.initials: D
authors.lastname: Middleton
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: J
authors.initials: J
authors.lastname: McCluskey
authors.forename: P
authors.initials: P
authors.lastname: Parham
authors.forename: K
authors.initials: K
authors.lastname: Lienert-Weidenbach
mesh_terms: D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D005786:Gene Expression Regulation / Q000276:immunology*; D015894:Genome, Human; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D006680:HLA Antigens; D012333:RNA, Messenger