Molecular Approaches to Analysis of X-Linked Immunodeficiencies

Abstract

Although the X-linked immunodeficiencies—X-linked agammaglobulinemia (XLA), X-linked severe combined immunodeficiency (XSCID), Wiskott-Aldrich syndrome (WAS), X-linked lymphoproliferative syndrome and X-linked hyper IgM syndrome—have been mapped to loci distributed throughout the X chromosome, they have several features in common that suggest that they might be members of a gene family: (i) all are maintained in the population at approximately the same gene frequency; (ii) expression of each defect is limited to the hematopoieticsy stem; (iii) atypical forms of each disorder have been described; and (iv) obligate carriers of these disorders are normal by all immunologic criteria. The failure of carriers of XLA, XSCID, and WAS to show signs of their gene defects can be explained by the preferential use of the normal, nonmutant X as the active X in the cell lineages affected by the gene defects. These three disorders also share an additional feature; in boys with XLAX, SCID, or WAS there is asynchronous expression of cell surface markers of differentiation or activation. If some or all of the genes that are abnormal in the X-linked immunodeficiencies are members of a gene family, then isolation of one gene may lead to the others.