Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency. Defects of the gamma(c)-JAK3 signaling pathway as a model

Cytokines play a major role in lymphoid development. Defects of the common gamma chain (gamma (c)) or of the JAK3 protein in humans have been shown to result in a severe combined immune deficiency (SCID), with a profound defe ct in T and natural killer (NK)-cell development, whereas B-cell generation is apparently unaffected (T-B+NK- SCID). While extensive molecular and bio chemical analysis of these patients has been instrumental in understanding better the biological properties of the gamma (c) and JAK3 protein, an unex pected phenotypic heterogeneity of gamma (c) and JAK3 deficiency has emerge d, indicating the need for appropriate and extensive investigations even in patients with atypical presentations. At the same time, characterization o f the defects has been instrumental in the development of never therapeutic approaches, from in utero hematopoietic stem cell transplantation to gene therapy.