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.