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

Mella, Patrizia; Schumacher, Richard Fabian; Cranston, Treena; Basile, Geneviève de Saint; Savoldi, Gianfranco; Notarangelo, Luigi D.

doi:10.1002/humu.1199

Cited by 29 publications

(26 citation statements)

References 21 publications

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“…The observed phenotype of del58A and D169E mutant proteins is explained by the fact that each resides within the 300-amino acid N-terminal FERM domain of JAK3 that mediates receptor binding and regulates catalytic activity of the distal C-terminal kinase domain. [36][37][38][39] G589S resides within the JH2 domain, the site of the largest number of reported JAK3 sequence abnormalities with 3 of 9 mutations in the present series and 13 of 27 mutations reported from SCID patients in Europe 41,55 involving this region. Previous reports demonstrated that, like the G589S mutant protein examined in this report, SCID patient JH2 domain mutations C759R and del586-592 each associated normally with ␥c but lacked in vitro kinase activity.…”

Section: Discussionmentioning

confidence: 55%

“…These JH1 domain mutations are distinct from the 3 previously reported L910S, Y1023X, and C1024fsX1037 kinase domain mutations. 41,55 As previously mentioned, no JAK3 mutations have been found to date in patient 5 following sequence analysis of the cDNA open reading frame, all exons and surrounding intron splice sites in genomic DNA, and potential regulatory elements (J.O'S., unpublished data, June 2003). This individual may prove to have mutations in as yet to be identified cis-acting JAK3 regulatory elements or other genes encoding proteins that positively regulate JAK3 expression.…”

Section: Discussionmentioning

confidence: 95%

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Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation

Roberts

Lengi

Brown

et al. 2004

Blood

113

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 95%

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation

Roberts

Lengi

Brown

et al. 2004

Blood

113

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“…In addition to mutations in the JH3 and JH2 domain, single point mutations in the JH1 kinase domain (at least those affecting the last tyrosine residue at codon 1023) have also been shown to abolish phosphorylation [Mella et al, 2001].…”

Section: Mutations and Polymorphismsmentioning

confidence: 99%

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

et al. 2001

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During the last 10 years, an increasing number of genes have been identified 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 cytokine receptors which share the common gamma chain. Defects of this gene cause an autosomal recessive form of severe combined immunodeficiency with almost absent T-cells and functionally defective B-cells (T(-)B(+) SCID). Herewith, we present molecular information on the first 27 unique mutations identified in the JAK3 gene, including clinical data on all of the 23 affected patients 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 atypical clinical and immunological features. Development of a structural model of the JAK3 kinase domain has allowed characterization of the functional effects of the various mutations. Most importantly, molecular analysis at the JAK3 locus results in improved genetic counseling, allows early prenatal diagnosis, and prompts appropriate treatment (currently based on hematopoietic stem cell transplantation) in affected families.

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“…4 The phenotype of patients with ␥c and Jak3 mutations is virtually identical; they present with no T or natural killer cells and a normal number of poorly functioning B cells (T Ϫ B ϩ NK Ϫ SCID). [5][6][7][8] Human SCID patients do not produce specific antibodies in response to in vivo antigenic challenge, and the disease usually presents in infants as an array of opportunistic infections and mortality in the first 2 years of life. Human SCID is currently treated by reconstitution of the immune defenses with hematopoietic stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog

Boggon

Manley

et al. 2005

Blood

154

110

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Jak (Janus kinase) family nonreceptor tyrosine kinases are central mediators of cytokine signaling. The Jak kinases exhibit distinct cytokine receptor association profiles and so transduce different signals. Jak3 expression is limited to the immune system, where it plays a key role in signal transduction from cytokine receptors containing the common gammachain, ␥c. Patients unable to signal via ␥c present with severe combined immunodeficiency (SCID). The finding that Jak3 mutations result in SCID has made it a target for development of lymphocytespecific immunosuppressants. Here, we present the crystal structure of the Jak3 kinase domain in complex with staurosporine analog AFN941. The kinase domain is in the active conformation, with both activation loop tyrosine residues phosphorylated. The phosphate group on pTyr981 in the activation loop is in part coordinated by an arginine residue in the regulatory C-helix, suggesting a direct mechanism by which the active position of the C-helix is induced by phosphorylation of the activation loop. Such a direct coupling has not been previously observed in tyrosine kinases and may be unique to Jak kinases. The crystal structure provides a detailed view of the Jak3 active site and will facilitate computational and structure-directed approaches to development of Jak3-specific inhibitors. ( IntroductionThe Janus kinase (Jak) family of cytoplasmic tyrosine kinases are essential for signal transduction from a wide variety of cell-surface receptors. There are 4 members of the family in vertebrates: Jak1, Jak2, Jak3, and tyrosine kinase 2 (Tyk2). 1,2 Jak kinases share a characteristic domain architecture, which includes an aminoterminal FERM domain (Band 4.1, Ezrin, Radixin, Moesin homology domain), an src homology 2 (SH2)-like region, a pseudokinase domain, and a carboxy-terminal kinase domain. Parts of these structural domains have historically been termed Jak homology (JH) domains 1 through 7, based on primary sequence alignments. The FERM domain mediates association with the cytoplasmic region of cytokine receptors and may also participate in catalytic regulation. The function and activity of the SH2-like region is unclear. The pseudokinase (or JH2) domain is unique to Jak kinases. This domain is thought to have a protein kinase fold but to lack catalytic activity, as residues critical for phosphotransfer are absent. The pseudokinase domain has been shown to be intrinsic to the autoregulation of Jak kinases via a direct interaction with the kinase domain. 3 The JH1 kinase domain lies at the C-terminus and is a functional tyrosine kinase. To date, no 3-dimensional structure has been reported for any portion of any of the Jak kinases.A wide variety of cytokine receptor superfamily members signal via the Jak/Stat (signal transducer and activator of transcription) pathway, including granulocyte colony-stimulating factor (G-CSF), thrombopoietin, the interferons, erythropoietin, and the interleukins. The Jak/Stat pathway is consequently involved in regulation of diverse cell proc...

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

Cited by 29 publications

References 21 publications

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation

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

Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog

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