Mutational analysis of the HLA-DQ3.2 insulin-dependent diabetes mellitus susceptibility gene.

Abstract

The human major histocompatibility complex includes approximately 14 class II HLA genes within the HLA-D region, most of which exists in multiple allelic forms. One of these genes, the DQ3:2.beta. gene accounts for the well-documented association of HLA-DR with insulin-dependent diabetes mellitus and is and is the single allele most highly correlated with this disease. We analyzed the amino acid substitutions that lead to the structural differences distinguishing DQ3-2.beta. from its nondibetogenic, but closely related allele, DQ3.1.beta.. Site directed mutagenesis of the DQ3.2.beta. gene was used to convert key nucleotides into DQ3.1.beta. condons. Subsequent expression studies of these mutated DQ303.beta. clones using retroviral vectors defined amino acid 45 as critical for generating serologic epitopes characterizing the DQw3.1.beta. and DQw3.2.beta. molecules.