The tenth known cause of human SCID is reported in this issue of the JCI by de Saint Basile et al. The relative frequencies of these different molecular types of human SCID may vary in other geographic areas. This is followed by adenosine deaminase deficiency in 16.1% of cases and IL-7Rα–chain deficiency in 10.3% of cases. The most common form of human SCID is the X-linked type, caused by mutations in IL-2RG, which accounts for 46% of cases at the author’s institution, the Duke University Medical Center (Figure 1). The gene products of 3 of these mutated genes are components of cytokine receptors (the IL-2 receptor γ chain that is also shared with 5 other cytokine receptors, JAK3, the primary signal transducer from the common γ chain, and the α chain of the IL-7 receptor) the products of 5 more genes (RAG1, RAG2, Artemis, CD3δ, and CD3ε) are necessary for antigen-receptor development the product of one gene (adenosine deaminase) is necessary for detoxification of metabolic products of the purine salvage pathway that cause lymphocytes to apoptose and the final gene encodes CD45, a phosphatase that serves as a critical regulator of signaling thresholds in immune cells (Table 1) ( 12). It is now known that SCID can be caused in humans by mutations in at least 10 different genes (Table 1) ( 6– 11), and the likelihood is that there are other causes yet to be discovered. Advances in molecular biology and the Human Genome Project as well as increased knowledge of various components of the immune system through studies of mutant mice and humans with genetically determined immunodeficiencies have all contributed to this understanding. Over the past 11 years, remarkable progress has been made in elucidating several other causes of this syndrome ( 5). However, it was not until 21 years later, in 1993, that a second fundamental cause of the condition was found, i.e., the molecular basis of X-linked human SCID ( 3, 4). The first discovered molecular cause of human SCID, adenosine deaminase deficiency, was reported in 1972 ( 2). In many families there was an X-linked recessive mode of inheritance while in others an autosomal recessive mode of inheritance was observed.

This indicated that there was more than one cause for this fatal syndrome characterized by an absence of T cells and all adaptive immunity. In the ensuing years, differences were noted in inheritance patterns for SCID. Swiss infants with the condition were profoundly lymphopenic and died of infection before their first or second birthdays. Human SCID was first reported by Glanzmann and Riniker in 1950 ( 1). In this issue of the JCI, a report describes how complete deficiency of the CD3ε chain of the T cell antigen receptor/CD3 complex causes human SCID. Three such components are cytokine receptor chains or signaling molecules, five are needed for antigen receptor development, one is adenosine deaminase - a purine salvage pathway enzyme, and the last is a phosphatase, CD45. SCID, a syndrome characterized by the absence of T cells and adaptive immunity, can result from mutations in multiple genes that encode components of the immune system.

What chromosome does scids affect