The role of gene polymorphism in HLA class I splicing

Abstract

Among the large number of human leucocyte antigen (HLA) alleles, only a few have been identified with a nucleotide polymorphism impairing correct splicing. Those alleles show aberrant expression levels, due to either a direct effect of the polymorphism on the normal splice site or to the creation of an alternative splice site. Furthermore, in several studies, the presence of alternatively spliced HLA transcripts co-expressed with the mature spliced transcripts was reported. We evaluated the splice site sequences of all known HLA class I alleles and found that, beside the consensus GT and AG sequences at the intron borders, there were some other highly conserved nucleotides for the different class I genes. In this review, we summarize the splicing mechanism and evaluate what is known today about alternative splicing of HLA class I genes.

Next generation sequencing characterizes the extent of HLA diversity in an Argentinian registry population

“…The majority (92.8%) of the class I alleles differ from a previously characterized allele by a single nucleotide substitution and most (84.4% HLA‐A, 63.6% HLA‐B, 100% HLA‐C) exhibit variation in noncoding regions. None of the intron variants appear to be in a position to affect the RNA splicing motifs at the 5′ and 3′ ends of the introns although a complete analysis of each variant would be necessary to completely exclude its impact on the branch point sequence and rule out the formation of alternative splicing sites . Figure S1 shows the positioning of the 11 HLA‐A intron 5 variants relative to the RNA splicing motifs.…”

“…Ten splicing motifs at the 5 0 and 3 0 ends of the introns although a complete analysis of each variant would be necessary to completely exclude its impact on the branch point sequence and rule out the formation of alternative splicing sites. 22,23 Figure S1 shows the positioning of the 11 HLA-A intron 5 variants relative to the RNA splicing motifs. Substitutions impacting class I exon sequences predominantly alter the amino acid sequence; we found variation encoding amino acid substitutions in exon 3 (encoding α2 extracellular domain), exon 5 (transmembrane region), and exon 6 (cytoplasmic tail).…”

More than 150 novel variants of HLA class I genes detected in German Stem Cell Donor Registry and UCLA International Cell Exchange samples

“…Alleles A*29:02:01:04 , B*27:05:02:04Q , C*01:02:01:02 , C*02:02:02:07 , C*07:01:01:14Q , and C*15:02:01:08N have alterations at positions that are conserved throughout the HLA class I genes, including HLA‐A, ‐B, ‐C, E, ‐G, ‐H, ‐J, ‐K, and ‐L, suggesting that the splicing signal may be impaired. Moreover, the variations g.1850, G>A and g.477, A>T detected in A*29:02:01:04 and C*01:02:01:02 , respectively, disrupt the conserved sequence at the 5′ splice site CSG/GTRMSW . In contrast, the variation found in allele A*01:01:01:10 does not alter the consensus sequence, which makes it questionable whether exon splicing is influenced.…”

“…Moreover, the variations g.1850, G>A and g.477, A>T detected in A*29:02:01:04 and C*01:02:01:02, respectively, disrupt the conserved sequence at the 5 0 splice site CSG/GTRMSW. 9 In contrast, the variation found in allele A*01:01:01:10 does not alter the consensus sequence, which makes it questionable whether exon splicing is influenced. On the other hand, the variations found in A*26:01:01:06, B*15:01:01:11, B*15:07:01:02, C*02:02:02:10, and C*03:03:01:04 are not at conserved positions.…”

Characterization of three new HLA Class I Alleles in Spanish Caucasians, HLA‐A*02:620, HLA‐B*27:150 and HLA‐B*07:05:01:02

“…Mutations within intron regions have led to alterations in the splicing mechanism and cell surface expression in several HLA alleles (Voorter, Gerritsen, Growneweg, Wieten, & Tilanus, ).The impact that polymorphisms have in the splicing mechanism can be predicted by using splicing tools (Brunak, Engelbrecht, & Knudsen, ). In the present case, although B*07:05:01:02 expression was not analysed, the new single‐nucleotide polymorphism neither modifies the acceptor splice site nor generates an alternative splicing site.…”