HLA‐DRB4*01:14 is a null allele, and renamed HLA‐DRB4*01:14N

Abstract

Full‐length sequencing of HLA‐DRB4*01:14 showed the same splice site mutation as in HLA‐DRB4*01:03:01:02N.

HLA-DRB3/4/5 Matching Improves Outcome of Unrelated Hematopoietic Stem Cell Transplantation

“…This is sometimes observed in HLA-DRB1*01 that occasionally associates with HLA-DRB5 ( 7 ). In addition, HLA-DRB3/4/5 typing can be challenging due to the presence of unusual associations and non-expressed variants caused by polymorphisms in non-coding regions (e.g., HLA-DRB4*01:03:01:02N or HLA-DRB4*01:14N) ( 8 , 9 ).…”

RNA and protein expression analysis of HLA‐DQB1*03:01:01:21Q allele: A null allele renamed as HLA‐DQB1*03:01:01:21N

“…However, there are a reduced number of class II null alleles described with aberrant splicing mechanisms, probably due to that until now the number of alleles with complete genome sequence is relatively low. One of the most frequently occurring null‐allele in Caucasian populations is DRB4*01:03:01:02N caused by a splice site mutation in intron 1 20 and two other alleles have been described with the same alteration in the splice site, DRB4*01:03:01:13N and DRB4*01:14N 5 . Interestingly, not only alteration in the intron region can generate aberrant splice sites, exonic variants can also generate a new dominant splice site; A*01:11N shows a synonymous substitution at exon 3 that generates a new splice site that prevents translation into a correct and stable class I molecule, 21 A*23:19N shows a non‐synonymous mutations at the of exon 3, impairing correct splicing 22 and B*07:44N have a substitution at exon 4 that introduce a new and stronger splice donor site generating a truncated protein 23 …”

“…The HLA variants are usually generated through single nucleotide changes that in some cases may modify the amino acid sequence or even cause null expression of protein 3 . Null alleles (N) can be caused by insertions, deletions, or substitutions of one or more nucleotides in the gene leading to the generation of a stop codon, mutations in the promoter region or in the highly conserved splicing region, thus preventing a translation of the coding sequence into a mature protein 4,5 . Other abnormally expressed HLA variants include secreted (S) alleles, encoding for proteins that are expressed as secreted molecules only, lowly expressed (L) alleles that are characterized by a low cell surface expression compared with normal levels, and questionable (Q) HLA alleles, which has a mutation that has previously been shown to have a significant effect on cell surface expression, but where this has not been confirmed 1 …”

Identification of a DRB1*04:07–DRB4*01:03:01:02N haplotype in a native American individual

“…The DRB4 gene encodes for the DR53 antigen which is in strong linkage disequilibrium with DRB1*04 , DRB1*07 , and DRB1*09 , however, certain polymorphisms in the DRB4 gene lead to a null phenotype (lack of cell surface expression). As of March 2022 (IPD—IMGT/HLA Database 3.47.0), 23 HLA‐DRB4 null alleles have been described, 1–7 the majority caused by a point mutation in exon 2 of the DRB4 gene (Table 1, http:// http://hla.alleles.org/alleles/nulls.html). The DRB4*01:03:01:02N allele, first described in 1989, is characterized by a point mutation in the acceptor splice site at the 3′ end of the first intron (AG > AA), leading to incorrect processing of the mRNA transcript and resulting in a non‐expressed allele 5,6 .…”

“…The DRB4 gene encodes for the DR53 antigen which is in strong linkage disequilibrium with DRB1*04, DRB1*07, and DRB1*09, however, certain polymorphisms in the DRB4 gene lead to a null phenotype (lack of cell surface expression). As of March 2022 (IPD-IMGT/HLA Database 3.47.0), 23 HLA-DRB4 null alleles have been described, [1][2][3][4][5][6][7] the majority caused by a point mutation in exon 2 of the DRB4 gene (Table 1, http://hla.alleles.org/alleles/nulls. html).…”