A novel mutation of intron 22 in Janus kinase 3–deficient severe combined immunodeficiency

Mjaanes, Christopher M.; Hendershot, Richard W.; Quinones, Ralph; Gelfand, Erwin W.

doi:10.1016/j.jaci.2007.03.004

Cited by 5 publications

(2 citation statements)

References 9 publications

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“…Mutations in TYK2, JAK3, STAT1 and STAT5b result in human immunodeficiencies, [6][7][8] underscoring the critical role of the JAK/STAT pathways in many biological systems. More specifically, JAK3 mutations have been linked to severe combined immunodeficiency in humans, [9][10][11] and JAK3 knockout mice have defects in T, B and NK cell development and function. 12 Thus, JAK3 offers applications as a target in the treatment of inflammation, allergy, autoimmune diseases and organ transplant rejection.…”

Section: Introductionmentioning

confidence: 99%

Structural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6

Chrencik

Patny

Leung

et al. 2010

Journal of Molecular Biology

202

177

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Section: Introductionmentioning

confidence: 99%

Structural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6

Chrencik

Patny

Leung

et al. 2010

Journal of Molecular Biology

202

177

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“…To date, the majority of JAK3‐SCID patients were compound heterozygous and the remaining patients were homozygous as result of parental consanguinity (Lee et al., ; Mjaanes, Hendershot, Quinones, & Gelfand, ; Notarangelo et al., ; Qamar et al., ; Roberts et al., ; Scarselli et al., ; Stepensky et al., ; Uchiyama et al., ). Although the most frequent defect resulted in a marked reduction or complete absence of the JAK3 protein expression/function, patients with missense mutations and a reduced JAK3 functional activity could show an atypical and less severe immunological phenotype (Frucht et al., ; Scarselli et al., ).…”

Section: Introductionmentioning

confidence: 99%

JAK3 mutations in Italian patients affected by SCID: New molecular aspects of a long‐known gene

Matteo

Chiriaco

Scarselli

et al. 2018

Molec Gen & Gen Med

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BackgroundMutations in the Janus Kinase 3 (JAK3) gene cause an autosomal recessive form of severe combined immunodeficiency (SCID) usually characterized by the absence of both T and NK cells, but preserved numbers of B lymphocytes (T‐B+NK‐SCID). The detection of larger (>100 bp) genomic duplications or deletions can be more difficult to be detected by PCR‐based methods or standard NGS protocols, and a broad range of mutation detection techniques are necessary.MethodsWe report four unrelated Italian patients (two females and two males) with SCID phenotype. Protein expression, functional studies, molecular analysis by standard methods and NGS, and transcripts studies were performed to obtain a definitive diagnosis.ResultsHere, we describe four JAK3‐deficient patients from four unrelated families. The first patient is homozygous for the known c.1951 C>T mutation causing the amino acidic change p.R651W. The other two patients, originating from the same small Italian town, resulted compound heterozygotes for the same g.15410_16542del deletion and two different novel mutations, g.13319_13321delTTC and c.933T>G (p.F292V), respectively. The fourth patient was compound heterozygous for the novel mutations p.V599G and p.W709R. Defective STAT5 phosphorylation after IL2 or IL15 stimulation corroborated the mutation pathogenicity. Concerning g.15410_16542del mutation, probably due to an unequal homologous recombination between Alu elements of JAK3 gene, microsatellites analysis revealed that both unrelated Pt2 and Pt3 and their carrier family members shared the same haplotype. These data support the hypothesis of a founder effect for the g.15410_16542del mutation that might have inherited in both unrelated families from the same ancient progenitor.ConclusionDifferent molecular techniques are still required to obtain a definitive diagnosis of AR‐SCID particularly in all cases in which a monoallelic mutation is found by standard mutation scanning methods.

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The regulation of JAKs in cytokine signaling and its breakdown in disease

et al. 2019

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The JAK-STAT signal transduction pathway is responsible for mediating signals of over fifty cytokines, growth factors and hormones. Signaling through the JAK-STAT pathway is regulated on multiple levels, including intramolecular regulation by the JAK pseudokinase domain, and intermolecular regulation by a host of regulatory proteins. The advent of accessible genomic tools have provided a wealth of information on disease-associated mutations in the JAK-STAT pathway and its regulatory components. The vast number of these mutations in diseases ranging from immunodeficiencies and obesity to many cancers highlight the importance of correct regulation of JAK-STAT signaling for biological processes such as hematopoiesis, regulation of the immune system, metabolism, and growth. Simultaneously, JAK inhibitors are gaining traction in clinical use, both for treatment of diseases driven by JAK mutations, and for a host of inflammatory disorders, in which proinflammatory cytokine signaling through the JAK-STAT pathway is an integral part of pathogenesis. The elucidation of molecular mechanisms in the pathogenesis of complex diseases has also, however, brought the limitations of our current understanding on the regulation of cytokine signaling to the foreground. Indeed, deeper understanding of these regulatory mechanisms are a prerequisite for the development of the next generation of pharmacological modulators of the JAK-STAT pathway. In this review we discuss the current state of knowledge of the intra- and intermolecular regulation of the JAK-STAT pathway, with a focus on diseases arising from disruptions in the regulatory apparatus.

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A novel mutation of intron 22 in Janus kinase 3–deficient severe combined immunodeficiency

Cited by 5 publications

References 9 publications

Structural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6

Structural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6

JAK3 mutations in Italian patients affected by SCID: New molecular aspects of a long‐known gene

The regulation of JAKs in cytokine signaling and its breakdown in disease

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