Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility

Couturier, Nicolas; Bucciarelli, Florence; Nurtdinov, Ramil; Debouverie, Marc; Lebrun-Frénay, Christine; Defer, Gilles; Moreau, Thibault; Confavreux, Christian; Vukusic, Sandra; Cournu-Rebeix, Isabelle; Goertsches, Robert; Zettl, Uwe K.; Comabella, Manuel; Montalbán, Xavier; Rieckmann, Peter; Weber, Frank; Müller‐Myhsok, Bertram; Edan, Gilles; Fontaine, Bertrand; Mars, Lennart T.; Saoudi, Abdelhadi; Oksenberg, Jorge R.; Clanet, M.; Liblau, Roland; Brassat, David

doi:10.1093/brain/awr010

Cited by 94 publications

(81 citation statements)

References 59 publications

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“…21 Analysis of protein-protein interactions by STRING 22 highlighted an interaction of TYK2 with many of the associated MS genes identified by GWA studies (figure 3) including IL7R and STAT3, lending further support for the involvement of TYK2 in MS risk and likely acting through an immune mechanism. It is intriguing that the previously known MS-associated SNP, rs34536443, is considered a protective allele, whereas we provide evidence that rs55762744 confers risk to MS within this family.…”

Section: Discussionmentioning

confidence: 87%

“…A recent study has shown the protective allele to alter tyrosine kinase activity and modify the cytokine profile to a T H 2 phenotype. 21 It may be common to see both protective and susceptibility alleles at the GWAS-associated genes akin to the variants observed at the MHC. An example would be HLA-DRB1*15 that acts as a susceptibility allele while HLA-DRB1*14 acts as a protective allele.…”

Section: Discussionmentioning

confidence: 99%

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Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene

Dyment

Cader²,

Chao³

et al. 2012

Neurology

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Objective: To identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations. Methods:We performed exome sequencing in a subset of affected individuals to identify novel variants contributing to MS risk within this unique family. The candidate variant was genotyped in a validation cohort of 2,104 MS trio families.Results: Four family members with MS were sequenced and 21,583 variants were found to be shared among these individuals. Refining the variants to those with 1) a predicted loss of function and 2) present within regions of modest haplotype sharing identified 1 novel mutation (rs55762744) in the tyrosine kinase 2 (TYK2) gene. A different polymorphism within this gene has been shown to be protective in genome-wide association studies. In contrast, the TYK2 variant identified here is a novel, missense mutation and was found to be present in 10/14 (72%) cases and 28/60 (47%) of the unaffected family members. Genotyping additional 2,104 trio families showed the variant to be transmitted preferentially from heterozygous parents (transmitted 16: not transmitted 5; 2 ϭ 5.76, p ϭ 0.016).Conclusions: Rs55762744 is a rare variant of modest effect on MS risk affecting a subset of patients (0.8%). Within this pedigree, rs55762744 is common and appears to be a modifier of modest risk effect. Exome sequencing is a quick and cost-effective method and we show here the utility of sequencing a few cases from a single, unique family to identify a novel variant. Multiple sclerosis (MS) is a common, complex, neurologic condition with both environmental and genetic factors contributing to risk. Epidemiologic studies have highlighted the significant influence of latitude on MS prevalence and Epstein-Barr virus infection, smoking, and low vitamin D levels are strongly implicated environmental risk factors. 1,2 Genetic contributions are clear from family studies with 15%-20% of individuals with MS having an affected relative.3 Furthermore, monozygotic twins have a 25% concordance rate as compared to the 5% seen in dizygotic twins. 4 These and other familial studies have demonstrated that genes contribute significantly to the familial aggregation of MS.Despite a strong genetic component, it is extremely rare to find families with 5 or more individuals with MS in successive generations. We previously reported a family with up to 15 individuals with MS.5 MS was present in 4 generations and penetrance was relatively consistentFrom The

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene

Dyment

Cader²,

Chao³

et al. 2012

Neurology

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“…Moreover, it is increasingly clear that the functional impact of many polymorphisms, notably in immune response imbalance, can differ according to cell or tissue types and their particular biological state. A modest reduction of IFN-b signaling has been observed in ex vivo-expanded T cells from heterozygote Tyk2 P1104A carriers (16). As this is not the case in heterozygote B cell lines and reconstituted fibroblasts, it suggests that this Tyk2 variant may have a differential impact depending on cell type.…”

mentioning

confidence: 97%

“…Many SNPs are in the coding region, and .100 nonsynonymous variants have been annotated. Genome-wide association studies and more targeted candidate approaches have shown strong linkage of Tyk2 haplotypes or individual SNPs to systemic and organ-specific autoimmune diseases, namely systemic lupus erythematosus (SLE) (11)(12)(13)(14), multiple sclerosis (MS) (15)(16)(17)(18)(19), Crohn's disease (20)(21)(22), psoriasis (23), type 1 diabetes (24), endometriosis-related infertility (25), and primary biliary cirrhosis (26) (Table I). Interestingly, one rare MSassociated variant (rs34536443) is considered to be protective, whereas another (rs55762744) was recently identified as a risk allele (17).…”

mentioning

confidence: 99%

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Gakovic

Ragimbeau

et al. 2013

The Journal of Immunology

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Tyk2 belongs to the Janus protein tyrosine kinase family and is involved in signaling of immunoregulatory cytokines (type I and III IFNs, IL-6, IL-10, and IL-12 families) via its interaction with shared receptor subunits. Depending on the receptor complex, Tyk2 is coactivated with either Jak1 or Jak2, but a detailed molecular characterization of the interplay between the two enzymes is missing. In human populations, the Tyk2 gene presents high levels of genetic diversity with >100 nonsynonymous variants being detected. In this study, we characterized two rare Tyk2 variants, I684S and P1104A, which have been associated with susceptibility to autoimmune disease. Specifically, we measured their in vitro catalytic activity and their ability to mediate Stat activation in fibroblasts and genotyped B cell lines. Both variants were found to be catalytically impaired but rescued signaling in response to IFN-α/β, IL-6, and IL-10. These data, coupled with functional study of an engineered Jak1 P1084A, support a model of nonhierarchical activation of Janus kinases in which one catalytically competent Jak is sufficient for signaling provided that its partner behaves as proper scaffold, even if inactive. Through the analysis of IFN-α and IFN-γ signaling in cells with different Jak1 P1084A levels, we also illustrate a context in which a hypomorphic Jak can hamper signaling in a cytokine-specific manner. Given the multitude of Tyk2-activating cytokines, the cell context–dependent requirement for Tyk2 and the catalytic defect of the two disease-associated variants studied in this paper, we predict that these alleles are functionally significant in complex immune disorders.

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“…Recent genome-wide association studies demonstrated that single-nucleotide polymorphisms (SNPs) in genes involved in T H cell activation and maturation are over-represented in MS, implicating particularly T H cell differentiation and polarization in MS pathogenesis 3 . Despite the large number of risk factors identified, reports about the underlying molecular mechanisms and their actual contribution to the aetiology of MS remain rare [4][5][6] .…”

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confidence: 99%

Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells

et al. 2014

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Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility

Cited by 94 publications

References 59 publications

Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene

Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells

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