Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency.

Schmalstieg, F. C.; Leonard, Warren J.; Noguchi, Masayuki; Berg, Maria; Rudloff, Helen E.; Denney, Richard M.; Dave, Sanat K.; Brooks, Edward G.; Goldman, Armond S.

doi:10.1172/jci117765

Cited by 86 publications

(51 citation statements)

References 27 publications

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“…The majority of previously characterized mutations in JAK3 or ␥ c result in SCID either by abolishing the expression of JAK3 or ␥ c or by disrupting the JAK3-␥ c interaction (2,27,32,38,40). Our study provides an alternative mechanism and suggests that disruption of the regulatory function of the JH2 domain of JAK3 can also lead to a SCID phenotype.…”

Section: Discussionmentioning

confidence: 69%

“…It is well established that JAK3-␥ c interaction is vital for IL-2 signaling (5, 31, 37). Several naturally occurring mutations of ␥ c which affect its association with JAK3 cause X-SCID or X-linked combined immunodeficiency (32,37,40). Although our previous studies indicate that the JH2 domain of JAK3 is dispensable for receptor association (5), it was still possible that global deformity of the protein structure by the patients' specific mutations disrupted the binding of the mutant JAK3 to ␥ c and thus abolished IL-2 signaling.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Complex Effects of Naturally Occurring Mutations in the JAK3 Pseudokinase Domain: Evidence for Interactions between the Kinase and Pseudokinase Domains

Chen

Cheng

Candotti

et al. 2000

Molecular and Cellular Biology

123

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The structure of Janus kinases (JAKs) is unique among protein tyrosine kinases in having tandem, nonidentical kinase and pseudokinase domains. Despite its conservation in evolution, however, the function of the pseudokinase domain remains poorly understood. Lack of JAK3 expression results in severe combined immunodeficiency (SCID). In this study, we analyze two SCID patients with mutations in the JAK3 pseudokinase domain, which allows for protein expression but disrupts the regulation of the kinase activity. Specifically, these mutant forms of JAK3 had undetectable kinase activity in vitro but were hyperphosphorylated both in patients' Epstein-Barr virus-transformed B cells and when overexpressed in COS7 cells. Moreover, reconstitution of cells with these mutants demonstrated that, although they were constitutively phosphorylated basally, they were unable to transmit cytokine-dependent signals. Further analysis showed that the isolated catalytic domain of JAK3 was functional whereas either the addition of the pseudokinase domain or its deletion from the full-length molecule reduced catalytic activity. Through coimmunoprecipitation of the isolated pseudokinase domain with the isolated catalytic domain, we provide the first evidence that these two domains interact. Furthermore, whereas the wild-type pseudokinase domain modestly inhibited kinase domain-mediated STAT5 phosphorylation, the patient-derived mutants markedly inhibited this phosphorylation. We thus conclude that the JAK3 pseudokinase domain is essential for JAK3 function by regulating its catalytic activity and autophosphorylation. We propose a model in which this occurs via intramolecular interaction with the kinase domain and that increased inhibition of kinase activity by the pseudokinase domain likely contributes to the disease pathogenesis in these two patients.Cytokines are critical regulators of cellular growth and differentiation, a subset of which bind to members of the type I cytokine receptor superfamily and initiate their actions by ligand-induced receptor oligomerization (23). Although cytokine receptors lack intrinsic kinase activity, they associate with and activate cytoplasmic protein tyrosine kinases (PTKs), which then phosphorylate downstream signaling molecules such as the signal transducers and activators of transcription (STATs). Activated STATs, in turn, translocate to the nucleus and regulate gene expression (7,17,35).The Janus kinase (JAK) family of nonreceptor PTKs are critical elements in cytokine signaling (7, 17). Of four mammalian members (JAK1, JAK2, JAK3, and TYK2) identified so far (35), JAK3 is unique in its predominant expression in hematopoietic cells (13,20,45) and its ability to specifically associate with the common gamma chain (␥ c ) of cytokine receptors through its N terminus (1,5,31,37). JAK3 is activated by interleukin 2 (IL-2), , which all utilize ␥ c as a component of their receptors (23). Mutation of JAK3 results in autosomal recessive severe combined immunodeficiency (JAK3-SCID) in humans and mice, illustrat...

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Section: Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Complex Effects of Naturally Occurring Mutations in the JAK3 Pseudokinase Domain: Evidence for Interactions between the Kinase and Pseudokinase Domains

Chen

Cheng

Candotti

et al. 2000

Molecular and Cellular Biology

123

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“…thymocytes with residual nonfunctional circulating T cells, as observed in IL-2 receptor α chain deficiency, and in some leaky forms of T -B + SCID caused by mutations of JAK3 or IL2RG genes (29,30). While the contributory role of hypothetical defects of central tolerance in these immunodeficiencies remains to be assessed, we hypothesize that Omenn syndrome may constitute a paradigmatic model of pathogenesis for more common autoimmune diseases associated with impaired T cell differentiation.…”

Section: Discussionmentioning

confidence: 94%

AIRE deficiency in thymus of 2 patients with Omenn syndrome

Cavadini¹,

Vermi²,

Facchetti³

et al. 2005

J. Clin. Invest.

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Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-β receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.

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“…The diagnosis of T-cell immunodeficiency is usually straightforward and should be confirmed by molecular genetic analysis when a patient is clinically immunodeficient and lab tests reveal an absence of T lymphocytes (16). Significant T-cell immunodeficiency should, however, be considered in clinically immunodeficient patients who present with an atypical immunologic phenotype as a result of residual autologous T cells (17,18), maternal T-cell engraftment (19), a leaky thymus with release of some T-cell clones (11), or of being part of combined immunodeficiency syndrome. In cases such as these, elaborate and intensive studies of the thymus, including assessment of recent thymic emigrant cells or analysis of the TCR repertoire, are required to estimate the severity and nature of the immune disorder (20).…”

Section: Discussionmentioning

confidence: 99%

Molecular Assessment of Thymus Capabilities in the Evaluation of T-Cell Immunodeficiency

et al. 2010

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T-cell immunodeficiency may pose a diagnostic challenge to clinicians, especially when the basic T-cell immune workup is not sufficiently informative. An intensive assessment of thymus capabilities that involves either measuring the recent thymic emigrant cells or analyzing the T-cell receptor (TCR) repertoire is often required to estimate the severity and nature of the immune disorder. A comprehensive T-cell immune workup, including TCR excision circles (TRECs) and TCR repertoire analyses, was performed in three patients with various degrees of severity of T-cell immunodeficiency. All three patients had normal peripheral CD3ϩ T lymphocytes. TCR repertoire analysis revealed oligoclonal (patient 1), restricted (patient 2), and near-normal (patient 3) patterns. TREC quantification was significantly reduced in patients 1 and 2 but normal in patient 3. Based on clinical features at presentation and at follow-up, and supported by the results of immunologic studies, patients 1 and 2 were diagnosed as having significant T-cell immunodeficiency and patient 3 as having T-cell immunocompetence. Assessment of thymus capabilities by TRECs and TCR repertoire analyses is helpful in diagnosing patients with T-cell immunodeficiency and should be part of the evaluation of every patient suspected of having that condition.

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Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency.

Abstract: Clin. Invest. 1995.95:1169-1173

Cited by 86 publications

References 27 publications

Complex Effects of Naturally Occurring Mutations in the JAK3 Pseudokinase Domain: Evidence for Interactions between the Kinase and Pseudokinase Domains

Complex Effects of Naturally Occurring Mutations in the JAK3 Pseudokinase Domain: Evidence for Interactions between the Kinase and Pseudokinase Domains

AIRE deficiency in thymus of 2 patients with Omenn syndrome

Molecular Assessment of Thymus Capabilities in the Evaluation of T-Cell Immunodeficiency

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