Elongation of the cytoplasmic domain, due to a point deletion at exon 7, results in an HLA‐C null allele, Cw*0409 N

Abstract

The development of molecular techniques for HLA typing has allowed the identification of genes previously assigned as serologic blank alleles. Lack or poor cell surface expression has been found for molecules coded by HLA-A, -B, -DRB4, -DRB5, and -DPB1 genes. In this report we describe the first HLA-C gene encoding for a null cell surface molecule. HLA-Cw*0409 N shows a point deletion at position 1095 within exon 7. This mutation provokes a codon reading shift, generating a new translation stop codon 97 bp downstream to that described in alleles normally expressed. This new stop codon location implies the presence of 32 extra amino acid residues in the cytoplasmic domain. Transfection experiments suggest that elongation of the cytoplasmic domain in Cw*0409 N would be the cause of cell surface expression failure, although Cw*0409 N heavy chain is able to create stable complexes with beta2-microglobulin. HLA-C fragment length analysis in a small selected group of samples with B44-Cblk haplotypic associations allowed us to identify two additional subjects showing both a serologic silent Cw*04 allele and a point base deletion at the 3' end of the HLA-C gene. This finding indicates that the allele frequency of Cw*0409 N within serologic C blank alleles would be appreciable, although basically restricted to the (A23)-Cw*0409 N-B*4403-DR7-DQ2 haplotype.

HLA Class I: An unexpected role in integrin β4 signaling in endothelial cells

“…An extreme example is HLA-C*04:09N. This allele has a point deletion in exon 7 which shifts the open reading frame, and causes elongation of the cytoplasmic domain and failed surface expression [75]. Polymorphisms in the HLA-I molecule may also affect its association with integrin β4.…”

Extensive haplotype diversity in African American mothers and their cord blood units

“… a The presence of C*04:09N was evaluated in 56 samples typed as C*04:01:01G including 35 carrying B*44:03, four of these with A*23 (31) and one with a haplotype identical to that observed carrying C*04:09N, A*02:01~B*4403~DRB1*07~DQB1*02 (32). The nonexpressed allele was not observed.…”

Group-Specific Amplification of cDNA From DRB1 Genes. Complete Coding Sequences of Partially Defined Alleles and Identification of the New Alleles DRB1*040602, DRB1*111102, DRB1*080103, and DRB1*0113

“…However, those regions have demonstrated functional relevance, including polymorphisms associated to impaired or abolished expression in null alleles [5,6].…”