A loss-of-function mutation in exon1 of limited HLA class I alleles is common in patients with aplastic anemia

Abstract

Leukocytes that lack HLA allelic expression (HLA-LLs) caused by a copy-number-neutral loss of heterozygosity in the short arm of chromosome 6 (6pLOH) and somatic mutations in HLA class I genes are commonly identified in patients with acquired aplastic anemia (AA), although the exact mechanisms underlying the HLA loss and HLA class I allele repertoire likely to acquire loss-of-function mutations remain unknown due to the limited number of AA patients that have been studied for loss-of-function mutations in HLA class I genes. We identified a common nonsense mutation at codon19 (c.19C>T, p.R7X) in exon1 (Exon1mut) of different HLA-A and HLA -B alleles in HLA-LLs from AA patients. Screening of 353 Japanese patients with AA using a novel droplet digital PCR assay revealed Exon1mut in 101 (29%) of the patients. Exon1mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles that corresponded to 4 HLA supertypes (A02, A03, B07, and B44), suggesting that limited autoantigens presented by these HLA class I alleles to T cells are involved in AA development. These findings provide insight into the immune pathophysiology of BM failure and contribute to identify candidate autoantigens in AA.