Unexpected and variable phenotypes in a family with JAK3 deficiency

Abstract

Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vbeta family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.

Mutations in genes required for T-cell development:IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review

“…The authors speculate that other genetic factors may have affected the phenotypes in these siblings. 82 Other groups have also reported milder forms of JAK3 SCID. 14 Mutations in IL2RG that confer a mild SCID phenotype have also been identified.…”

“…40,79 Other patients, who had no ADA enzyme activity in erythrocytes, were immunologically normal as a result of activity in other cell types. 77,80,81 Frucht et al 82 have described two and possibly three siblings with identical mutations in JAK3 who had different clinical phenotypes. Each sibling had an A96G initiation start-site mutation that encoded a dysfunctional product and another allele with a splice donor-site mutation that is predicted to cause premature termination of JAK3.…”

Variable phenotypic expression of mutations in genes of the immune system

“…The routine use of molecular testing is unfortunately probably a few years off, considering that it is currently available primarily only in research laboratories and that newborn screening by available immunologic methods is not even performed for any of these conditions. Indeed, there is no screening (18) for any of these conditions at any time of life anywhere in the world. Until this happens, there will still be patients who present with recurrent infections who have undiagnosed, genetically determined immunodeficiency, the basis of which is unidentified.…”

“…Mutations in CD3ε were first reported to cause a relatively mild form of immunodeficiency (13), but more deleterious mutations were later found to cause SCID (14). Mutations in the genes encoding γc, ADA, and Jak3 usually result in SCID (15) but have also been shown to cause less severe forms of immunodeficiency (16)(17)(18). Clinical ambiguity also arises from the fact that seemingly identical clinical syndromes can be caused by mutations in different immune system genes.…”

A Targeted Deleterious Allele of the Splicing Factor SCNM1 in the Mouse

“…Splice-site mutations compose $15% of all diseasecausing mutations, and a similar number occur in splice enhancer and suppressor sequences (Nissim-Rafinia and Kerem 2005). Splice-site mutations are often associated with clinical heterogeneity within families, as described for Duchenne and Becker muscular dystrophy, cardiac sodium channelopathy (SCN5A), familial adenomatous polyposis (APC), severe combined immunodeficiency ( JAK3), and neurofibromatosis type 2 (NF2) (Kluwe et al 1998;Frucht et al 2001;Mohamed et al 2003;Rossenbacker et al 2005;Gurvich et al 2008). There is evidence that the clinical severity of these disorders is influenced by splicing efficiency.…”