Eleven novel JAK3 mutations in patients with severe combined immunodeficiency-including the first patients with mutations in the kinase domain.

Defects of the JAK3-gene are known to cause an autosomal recessive form of severe combined immunodeficiency with almost absent T-cells and functionally defective B-cells (T-B+SCID). The JAK3 protein, an intracellular tyrosine kinase, is crucial for signal-transmission from the common gamma chain to the Signal Transducers and Activators of Transcription (STATs) that drive gene expression in the nucleus. We present nine novel patients with eleven distinct mutations (g.96A>G, g.268G>C, IVS12-1G>A, g.2046C>T, g.2160C>T, g.2175G>A, g.2187G>T, g.2391C>T, g.2406C>T, IVS18+3G>C) among them a mutation in the kinase domain (JH1: g.3167del). The clinical phenotype of the patients shows an unusually broad spectrum ranging from classical SCID to almost normal. In order to understand the complex genotype-phenotype correlation we studied expression and function (by IL-2 induced phosphorylation) of the newly identified and two other alleles with JH1 mutations we recently reported. We found the first mutation in the JH1-domain of JAK3, that precludes kinase activity (L910S). The two other JH1 mutations both caused a premature stop. One of them (C1024fsX1037) also abolished any phosphorylation of JAK3 and expression of the protein. The other mutation (Y1023X), affecting the last JH1 tyrosine, may allow for residual protein expression and phosphorylation. This may indicate that the part of the kinase region downstream Y1023, is not essential for the function of JAK3.