Description of two new HLA-A alleles, HLA-A*02:572 and HLA-A*03:225 A. Balas, F. García-Sánchez & J. L. Vicario Departamento de Histocompatibilidad, Centro de Transfusión de la Comunidad de Madrid, Madrid, Spain Key words: A*02:572; A*03:225; HLA; SBT
Characterization of two new human-leukocyte antigen (HLA)-A alleles, A*02:572 and HLA-A*03:225. Two new human-leukocyte antigen (HLA)-A alleles were detected and subsequently characterized when low-resolution HLA typing was performed for related hematopoietic stem cell donor searching. In both cases, unexpected hybridization patterns were obtained when Luminex® (Luminex Corporation, Austin, TX) analysis was performed. HLA typing analysis of a patient (CTM-5030215) suffering from aplastic anemia suggested a novel HLA-A*02 allele segregating into the haplotype A*02 ∼ C*07 ∼ B*58 ∼ DRB1*13 ∼ DQB1*03. Confirmatory HLA-A typing by genomic full-length amplification and sequencing analysis of coding regions was carried out. The ABI3130 DNA-analyzer (Thermo Fisher Scientific, Waltham, MA) was used for electrophoresis and Assign 4.7 software (Conexio Genomics, Fremantle Western Australia, Australia) for HLA typing assignment. Two A*02 new-bearing related individuals were analyzed in order to confirm the sequence of the new HLA-A allele. Sequences alignment supported the presence of a new HLA-A*02 allele indicating a single point mutation within exon 3, codon 124 (ATC > GTC), when compared with the A*02:05:01 allele (1). This nucleotide variation results in a conservative coding change I124 > V (Figure 1A). The new
sequence (HWS10025174 – KP774530) has been officially defined as A*02:572 (2). Amino acid position 124 is highly conserved in classical HLA genes (1). Valine 124 instead of Isoleucine can be found only in A*02:215. Residue 124 is placed at the S3 β-strand of the α2 domain being involved in the peptide-binding specificity (3). Confirmatory sequencing of two hematological patient’s siblings (CTM-5030893 and CTM-1030346) gave a suggestive new HLA-A*03 allele. Assign 4.7 software and 3.19 IMGT/HLA database reported the presence of three mismatches in nucleotide positions 527, 538, 539 and 502, 524, 555, when compared with its most closely related alleles A*03:42 and A*03:66, respectively (Figure 1B). Complete coding sequencing in isolation confirmed the presence of a novel A*03 allele with two amino acid replacements, V152 > E and L156 > R regarding A*03:42. The new sequence has been officially defined as A*03:225 (HWS10025241, KR106299) (2). The haplotype including this new allele was the following: A*03:255 ∼ C*04 ∼ B*35 ∼ DRB1*01 ∼ DQB1*05. Nucleotide alignment suggests A*03:225 could had been raised as a result of interlocus recombination at exon 3 occurring between A*03:01:01 and most B*07, C*01, C*04, C*05, C*08 and C*14 alleles (Figure 1B). The comparison with the most frequent A*03 subtype, A*03:01:01, indicates four amino acid differences at the α-helix
Figure 1 (A) Partial protein sequence alignment of A*02:05:01 and A*02:572. (B) Exon 3 alignment of A*03:01:01, C*01:02:01, A*03:42, A*03:66 and A*03:225. Amino acid and nucleotide positions are indicated above.
regions of the α2 domain, 144 K > Q, 151 H > R, 156 L > R and 161 D > E, strongly suggesting differential allogeneic behaviour for this allele (3). The names A*02:572 and A*03:225 have been officially assigned by the World Health Organization (WHO) Nomenclature Committee in February and May 2015, respectively This follows the agreed policy that, subject to the conditions stated in the most recent Nomenclature Report (2), names will be assigned to new sequences as they are identified. List of such new names will be published in the following WHO Nomenclature Report. Correspondence
Antonio Balas PhD Departamento de Histocompatibilidad Centro de Transfusión de Madrid Avenida de la democracia s/n 28032 Madrid Spain Tel: 34 91 3017262 Fax: 34 91 3017253
We are most grateful to Elvira Trompeta, Rosalia Barragán and Guillermina Mezquita for their technical assistance.
Conﬂicts of interest
The authors have declared no conflicting interests. References 1. Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acid Res 2015: 43: D423–31. 2. Marsh SGE, Albert ED, Bodmer WF et al. Nomenclature for factors of the HLA system, 2010. Tissue Antigens 2010: 75: 291–455. 3. Reche PA, Reinherz EL. Sequence variability analysis of human class I and class II MHC molecules: functional and structural correlates of amino acid polymorphisms. J Mol Biol 2003: 331: 623–41.
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