[Molecular genetics of X-linked primary immunodeficiencies: advances in diagnosis and prevention]

Over the past 2 years, progress in medical genetics has brought about major advances in the field of primary immunodeficiencies. The genes underlying four X-linked defects in humans (X-linked agammaglobulinemia-XLA, X-linked severe combined immunodeficiency-XSCID, hyper IgM syndrome-HIGM1, and Wiskott-Aldrich syndrome- WAS), have recently been identified. These syndromes are all associated with increased susceptibility to infections due to defects of cell mediated and/or humoral immunity. The X-linked disorders described here are due to mutations in genes whose products are involved in fundamental steps in the development and maturation of lymphoid cells. XLA results from a defect in a non-receptor tyrosine kinase that is likely to be involved in a lineage-specific pathway of growth signal transduction. XSCID is due to a defect of the subunit gamma, common to a family of multichain lymphokine receptors (i.e., IL-2R; IL-4R). HIGM1 results from a partial failure of the interaction between T helper cells and B cells owing to mutation of the ligand (CD40L) expressed on T cells which normally interacts with B cell receptor CD40. The WAS protein has recently been identified as the mutated protein in the WAS, although it has not yet been fully characterized. Analysis of X-inactivation in different hematopoietic cell lineages of carrier females has been done to identify the lineage affected by the genetic defect: non random X-inactivation is observed in cell lines where the mutated protein plays a fundamental role. Moreover, X-inactivation analysis serves as a test to identify obligate carriers and to perform prenatal diagnosis. These results have enabled better understanding of the pathogenetic mechanisms underlying some immunodeficiencies and have laid the foundation for future therapeutic possibilities.