Evidence that X-linked severe combined immunodeficiency is not a differentiation defect of T lymphocytes

SUMMARY In order to gain information about the nature of the defect in X-linked severe combined immunodeficiency (XSCID). we investigated gene expression in different lymphoid and haematopoietic cells of female carriers by looking for non-random X chromosome usage. We have shown non-random X chromosome usage in T lymphocyte enriched (E+) fraction in all carriers. E cells and monocytes showed non-random X chromosome usage in three carriers tested. In the Bcell series one carrier showed non-random inactivalion in all EBV lines tested (10) and the same X chromosome was shown to be active in all cells, In other carriers there was a preference for use of the normal X chromosome but some B cell lines used the mutant X as well as the normal X. Similar results were found with granulocytes. In two female carriers DNA made directly from whole blood showed a non-random pattern of X chromosome usage. In fibroblast cultures from two female carriers more cells had the normal gene on the active X chromosome than had the defective gene on the active X chromosome. Within families there was heterogeneous expression of the gene. The gene that is defective in XSCID is expressed in all the cell types studied and. therefore, is not a T lymphocyte differentiation gene. The results are consistent with the gene being in a metabolic pathway as in certain autosomal recessive forms of SCID i.e. adenosine deaminase deficiency and purinc nucleosidc phosphorylase deficiency.