Polymorphism of the human alpha 1 immunoglobulin gene 3 ' enhancer hs1,2 and its relation to gene expression

We studied the hs1,2 transcriptional enhancer identified downstream of the human alpha1 gene of the immunoglobulin H (IgH) locus, for which two differ ent allelic configurations (a and b) were previously reported by Southern b lotting. By using a polymerase chain reaction (PCR) method we amplified min isatellites within the hs1,2 core enhancer, with variable numbers of tandem repeats (VNTR) defining three 'PCR alleles' alpha 1A, alpha 1B and alpha 1 C (including one, two and three repeats, respectively). Five different alph a1 h1,2 genotypes were encountered in a population of 513 donors, represent ing 13.8, 34.5, 49.7, 1.3 and 0.6% for the AA, BE, AB, AC and BC genotypes, respectively. Luciferase assays showed that increasing the number of minis atellites increased the transcriptional strength of the alpha1 hs1,2 enhanc er. Simultaneous determination of Southern blot alleles and VNTR alleles on ly showed a partial linkage between both types of polymorphism, altogether defining at least six different allelic forms of the 3'alpha1 region. In co nclusion, the present study further demonstrates the genetic instability of the 3'alpha region, for which multiple alleles have been generated through inversions and internal deletions and/or duplications. This study also str engthens the hypothesis that the polymorphism at the IgH 3' regulatory regi on of the alpha1 gene could play a role in the outcome of diseases involvin g immunoglobulin secretion.