Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency

During the last 10 years, an increasing number of genes have been identifie d whose abnormalities account for primary immunodeficiencies, with defects in development and/or function of the immune system. Among them is the JAK3 ,gene, encoding for a tyrosine kinase that is functionally coupled to cytok ine receptors which share the common gamma chain. Defects of this gene caus e an autosomal recessive form of severe combined immunodeficiency with almo st absent T cells and functionally defective B cells (T-B+ SCID). Herewith, we present molecular information on the first 27 unique mutations identifi ed in the JAK3 gene, including clinical data on all of the 23 affected pati ents reported so far. A variety of mutations scattered throughout all seven functional domains of the protein, and with different functional effects, have been identified. Availability of a molecular screening test, based on amplification of genomic DNA, facilitates the diagnostic approach, and has permitted recognition that JAK3 deficiency may also be associated with atyp ical clinical and immunological features. Development of a structural model of the JAK3 kinase domain has allowed characterization of the functional e ffects of the various mutations. Most importantly, molecular analysis at th e JAK3 locus results in improved genetic counseling, allows early prenatal diagnosis, and prompts appropriate treatment (currently based on hematopoie tic stem cell transplantation) in affected families. Hum Mutat 18:255-263, 2001. (C) 2001 Wiley-Liss,Inc.