THE RANDOM INACTIVATION OF THE X-CHROMOSOME CARRYING THE DEFECTIVE GENE RESPONSIBLE FOR X-LINKED HYPER IGM SYNDROME (X-HIM) IN FEMALE CARRIERS OF HIGM1

The molecular origin of X-linked hyper IgM syndrome has recently been identified as a defect in the ligand of CD40, gp39, a protein expresse d on the surface of activated T cells. The availability of detailed pe digrees for three families with affected males allowed assessment of t he random or nonrandom nature of the inactivation of the defective X c hromosome as well as a determination of the origin of the mutation. X chromosome inactivation was studied because of the relevance to the ab ility to detect carriers of HTGM1 and the potential for phenotypic eff ect in the carriers. Using immunostaining, PCR, and DNA sequencing, we found that the defective gene for gp39 is not selectively inactivated . Even in the presence of extremely skewed inactivation, normal levels of serum Ig mere found. In carriers in which the defective gene is pr edominantly expressed, staining alone revealed the carrier status reli ably while cloning and sequencing of the cDNA was necessary when the n ormal gene was predominantly expressed. Unlike some other X-linked def ects where extreme Lyonization may lead to disease, a small population of cells expressing the wild-type gp39 is sufficient to maintain norm al humoral immunity and prevent the clinical symptoms of X-HIM.