HLA class I allele (HLA-A2) expression defect associated with a mutation in its enhancer B inverted CAT box in two...

The present study shows a very highly diminished HLA-A2 cell surface expression with mendelian segregation in two nonrelated Spanish families. The associated haplotype included Cblank-B38-DRB1*1301-DQ6 in both families. cDNA sequence analysis in two members, one of each pedigree, revealed the presence of the commonest HLA-A2 allele (A*0201), without repetitive mutations that could indicate inappropriate or inefficient translation. Further, the coamplified 3'-untranslated region sequence was also the same described for HLA-A2. HLA-A transcription frequency by means of cDNA PCR-based cloning experiments and by Northern blotting pointed out a relatively low number of HLA-A2 mRNA molecules compared with the complementary HLA-A allele. 5'-Regulatory region sequences from two low-expressing HLA-A2 nonrelated individuals showed a unique and identical single point mutation at position -101 (T to C), when compared with all MHC class I alleles sequenced so far. Position -101 is located in the inverted CAT box associated with the MHC class I enhancer B. The fact that this is an extremely well-conserved position leads us to postulate that this change may be the only responsible for the defective expression of HLA-A2.