A nucleotide insertion in exon 4 is responsible for the absence of expression of an HLA‐A*01 allele

Abstract

HLA class I typing performed in parallel by molecular biology and serology has revealed cases where an HLA class I allele was identified whereas the corresponding antigen was not detected on the cell surface. In the present report, we describe four members of a family in whom an HLA-A1 allele identified at the molecular level was typed as A "blank" by lymphocytotoxicity. This serologically blank antigen was undetectable by isoelectric focusing (IEF). Sequencing of the HLA-A*01 allele from the promoter region to the eighth exonic region revealed insertion of a "C" nucleotide at the beginning of the fourth exon as compared to the common HLA-A*0101 allele. This mutation causes a frame shift, giving rise to an early stop codon in the fourth exon.

Inactivation of a functional HLA-A gene: A 4-kb deletion turns HLA-A*24 into a pseudogene

“…Fifty-one of these alleles are null alleles, which lack a serologically detectable product; three alleles show reduced cell surface expression (HLA-A*02:01:01:02L, A*24:02:01:02L, A*30:14L); and in two cases, the correct expression is questionable (HLA-A*32:11Q, A*23:19Q) [3]. The expression deficiency can be caused by point mutations giving rise to premature stop codons [4][5][6][7] deletions, or insertions leading to a frame shift and a premature termination [4,[8][9][10][11][12][13], deletions or mutations causing a structural defect in the molecule [14,15], mutations affecting transcription [16,17] and RNA splicing [4,8,18,19], or hypermethylation leading to gene inactivation [20].…”

No HLA-A gene detectable on one of the haplotypes in a caucasian family

“…The lack of expression can be different in origin: either point mutations giving rise to premature stop codons [4, 8 -10], deletions or insertions leading to a frame shift and a premature termination [4,5,[11][12][13][14], deletions causing a structural defect in the molecule [15], mutations affecting transcription [2,7], and RNA splicing [4 -6, 16]; or hypermethylation leading to gene inactivation [3].…”

Exon 5 Encoding the Transmembrane Region of HLA-A Contains a Transitional Region for the Induction of Nonsense-Mediated mRNA Decay

“…These null alleles have substitutions, insertions, or deletions that prevent or reduce the expression of an HLA class I molecule at the cell surface. To date some 25 HLA class I null alleles have been described (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). HLA class II null alleles are also known, but to a lesser extent than for class I (22)(23)(24)(25)(26)(27)(28)(29).…”