Molecular and biochemical characterization of JAK3 deficiency in a patient with severe combined immunodeficiency over 20 years after bone marrow transplantation: implications for treatment

Abstract

Summary. Severe combined immunodeficiency (SCID) comprises a heterogenous group of disorders that are fatal unless treated by bone marrow transplantation (BMT). The most common form of SCID (T−B+ SCID) is due to mutations of either the common gamma chain (γc) or of γc‐coupled JAK3 kinase. We report an unusual JAK3 defect in a female who was successfully treated >20 years ago with a BMT using her HLA‐identical father as the donor. Persistence of genetically and biochemically defective autologous B cells, associated with reconstitution of cellular and humoral immunity, suggests that integrity of the γc‐JAK3 signalling pathway is not strictly required for immunoglobulin production.

Molecular Modeling of the Jak3 Kinase Domains and Structural Basis for Severe Combined Immunodeficiency

“…R582 is exposed on the surface of the pseudokinase domain, and may be involved in intra-or intermolecular interactions which are destroyed when the charged side chain is substituted by a bulky, aromatic tryptophan. The other transcript detected in patient 7 misses 213 bp, corresponding to the whole exons 12 and 13 (30). This transcript encodes for an internally shortened protein, in which the kinase domain is misplaced as related to the Nterminus of Jak3.…”

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

“…The most frequent variant, X-linked SCID accounts only for approximately 60% of the cases (Rosen et al, 1995). However, patients with published mutations in the JAK3 gene, add up to scarcely a tenth of those with IL2RG mutations and are reported mostly (Macchi et al, 1995;Schumacher et al, 2000;Candotti et al, 1997;Bozzi et al, 1998;Villa et al, 1996) but not exclusively (Russell et al, 1995) from Europe. If this discrepancy is due to a reporting bias or to a geographic clustering remains to be seen.…”

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

“…The ability to test function of specific and expressed mutants in a phosphorylation assay using physiological substrates (JAK3 itself and STAT5) has enabled us to verify the consequences of the observed mutations [Candotti et al, 1997;Bozzi et al, 1998;Cacalano et al, 1999;Chen et al, 2000]. In fact, demonstration of JAK3 protein in Western assays does not rule out functional JAK3 deficiency until cytokine induced phosphorylation of JAK3 itself and/or STAT5 is excluded.…”

“…The R582W substitution leads to two different products, one of which has normal length but is not phosphorylated and the other one, with a 71 aa deletion in the downstream JH2 domain, is also expressed and can be phosphorylated, but is insufficient for signal transduction [Bozzi et al, 1998]. …”