The Replacement Mutation in HLA-DRB1*1211 Affects a Likely Keystone Position

Currently, 10 different amino acid variants of the HLA-DRB1*12 family are known. We here report the identification of a new HLA-DRB1*12 allele in a healthy Caucasian male individual. The allele was detected by sequencing-based typing during confirmatory high-resolution typing of an unrelated, male, potential donor from the Czech National Marrow Donors Registry. Compared with DRB1*120101, to which it is closest, the new variant is characterized by a new replacement mutation (T→C) at nucleotide position 126 of exon 2, resulting in the amino acid substitution Phe→Leu at position 47. Computational analysis reveals that position 47 functions as a keystone in the β1 domain, joining both segments of the α helix with the β sheet, and plays a major role in the structural conformation of the binding groove. Additionally, position 47 is part of pocket E of the peptide binding groove and is directly involved in peptide binding. The new allele, DRB1*1211, is therefore likely to differ substantially from other DRB1*12 alleles in its peptide binding repertoire and alloreactive potential.