The T cell regulator gene SH2D2A contributes to the genetic susceptibility of multiple sclerosis

Dai, Ke-Zheng; Hf, Harbo; Eg, Celius; Oturai, Annette Bang; Ps, Sørensen; Ryder, L. P.; Datta, Pameli; Svejgaard, A.; Hillert, Jan; Fredrikson, Sten; Sandberg‐Wollheim, Magnhild; Laaksonen, Mikko; Km, Myhr; Nyland, Harald; Vartdal, Frode; Spurkland, Anne

doi:10.1038/sj.gene.6363774

Cited by 48 publications

(47 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results suggest that the shortest allele (GA 13 ) of the SH2D2A gene promoter could contribute to the genetic susceptibility of JRA, similar to what we have observed in MS. 7 The associations of JRA and MS with less transcriptionally active short SH2D2A alleles support our notion that reduced expression of the immuneregulatory TSAd protein in activated T cells may increase the susceptibility to develop autoimmune diseases. The recent report that mice lacking the murine TSAd protein develop spontaneous autoimmune disease 4 lend support to this view.…”

supporting

confidence: 73%

“…Hence, individuals being homozygous for 'short' alleles of this GA repeat in the SH2D2A gene promoter display reduced expression of TSAd in activated T cells. 7 Moreover, there is an increased frequency of 'short' alleles (GA 13 and GA 16 ) among patients with multiple sclerosis (MS), suggesting that the SH2D2A gene may contribute to the genetic susceptibility to develop this disease. 7 This study was aimed to assess whether polymorphism of the SH2D2A gene promoter is also associated with juvenile rheumatoid arthritis (JRA).…”

mentioning

confidence: 99%

“…Methods: A SH2D2A gene segment containing the GA repeats was amplified by polymerase chain reaction (PCR) amplification as described previously. 7 The PCR products were separated on a 4.25% urea-polyacrylamide gel and identified according to size on an ABI 377XL DNA sequencer (PE Applied Biosystems, Foster City, CA, USA). The frequencies of alleles were compared by means of w 2 statistics or Fisher's exact test, when appropriate.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene

et al. 2004

Self Cite

View full text Add to dashboard Cite

T-cell-specific adapter protein (TSAd) involved in the negative control of T-cell activation is encoded by the SH2D2A gene. Our recent studies indicate that homozygosity for short (ie GA 13 and GA 16 ) alleles of the SH2D2A gene promoter is associated with development of multiple sclerosis. To study whether the same SH2D2A promoter polymorphism also contributes to the genetic susceptibility to develop juvenile rheumatoid arthritis (JRA), we examined 210 JRA patients and 558 healthy unrelated controls from Norway. The frequency of the short allele GA 13 was increased among the JRA patients compared to control (0.098 vs 0.05; P n ¼ 8 ¼ 0.042). There was a significant increased frequency of HLA-DRB1*08-positive patients carrying two copies of 'short' alleles GA 13 and/or GA 16 compared to healthy controls (16% vs 6%; P n ¼ 4 ¼ 0.016). Our data indicate that the 'short' alleles of the SH2D2A promoter could contribute to the genetic susceptibility to JRA.

show abstract

supporting

confidence: 73%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene

et al. 2004

Self Cite

View full text Add to dashboard Cite

show abstract

“…A key to understand the biological role of TSAd in T cells is probably its characterstic pattern of expression, since it is not expressed in naive resting T cells, but is rapidly induced upon stimulation of T cells [3,9,12,32]. This implies that whatever biological role TSAd serves in T cell signaling, it may not be involved in the first minutes or hours of signaling in naive T cells, since it is not present until at a later stage.…”

Section: Discussionmentioning

confidence: 99%

The C terminus of T cell‐specific adapter protein (TSAd) is necessary for TSAd‐mediated inhibition of Lck activity

et al. 2005

View full text Add to dashboard Cite

T cell-specific adapter protein (TSAd), encoded by the SH2D2A gene, is expressed in activated T cells. The function of TSAd is as yet unknown. We previously showed that TSAd may modulate T cell receptor-triggered signaling events. TSAd contains a Src homology (SH)2 domain, ten tyrosines and a C-terminal proline-rich region. Here, we show that human TSAd interacts with Lck through the Lck SH2 and SH3 domains and is a substrate for Lck. The TSAd C terminus, including the proline-rich region and five tyrosines, is both necessary and sufficient for TSAd interaction with and phosphorylation by Lck. Expression of TSAd in Jurkat TAg cells results in hyperphosphorylation of endogenous Lck on Y394 and to an even larger extent on Y505, resulting in a reduced Y394/Y505 phosphorylation ratio in these cells. Furthermore, full-length TSAd, but not TSAd lacking the C terminus, inhibits the hyperactive Lck Y505F mutant when both are expressed in Jurkat T cells. In contrast, expression of the TSAd C terminus alone is sufficient to inhibit Lck Y505F in phosphorylating its substrates in Jurkat T cells. Our results indicate that the TSAd C terminus is essential for inhibition of Lck activity by TSAd, and suggest a mechanism for how TSAd may inhibit early T cell activation events.

show abstract

“…The murine counterpart has been cloned as a binding partner for Itk and Rlk (14) and MEKK5, a mitogen-activated protein kinase kinase (15). We have also found that a GA repeat-length polymorphism in the promoter of the SH2D2A gene is associated with multiple sclerosis (16), suggesting that TSAd dysregulation may be associated with immunological disorders. In support of this idea, it was recently observed that mice lacking the murine TSAd gene develop spontaneous autoimmune disease with age (17).…”

mentioning

confidence: 74%

Transcriptional Activation of the SH2D2A Gene Is Dependent on a Cyclic Adenosine 5′-Monophosphate-Responsive Element in the Proximal SH2D2A Promoter

Dai

Johansen

Kolltveit³

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

The SH2D2A gene, encoding the T cell-specific adapter protein (TSAd), is rapidly induced in activated T cells. In this study we investigate the regulation of the SH2D2A gene in Jurkat T cells and in primary T cells. Reporter gene assays demonstrated that the proximal 1-kb SH2D2A promoter was constitutively active in Jurkat TAg T cells and, to a lesser extent, in K562 myeloid cells, Reh B cells, and 293T fibroblast cells. The minimal SH2D2A promoter was located between position −236 and −93 bp from the first coding ATG, and transcriptional activity in primary T cells depended on a cAMP response element (CRE) centered around position −117. Nuclear extracts from Jurkat TAg cells and activated primary T cells contained binding activity to this CRE, as observed in an EMSA. Consistent with this observation, we found that a cAMP analog was a very potent inducer of SH2D2A mRNA expression in primary T cells as measured by real-time RT-PCR. Furthermore, activation of SH2D2A expression by CD3 stimulation required cAMP-dependent protein kinase activity. Thus, transcriptional regulation of the SH2D2A gene in activated T cells is critically dependent on a CRE in the proximal promoter region.

show abstract

The T cell regulator gene SH2D2A contributes to the genetic susceptibility of multiple sclerosis

Cited by 48 publications

References 26 publications

Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene

Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene

The C terminus of T cell‐specific adapter protein (TSAd) is necessary for TSAd‐mediated inhibition of Lck activity

Transcriptional Activation of the SH2D2A Gene Is Dependent on a Cyclic Adenosine 5′-Monophosphate-Responsive Element in the Proximal SH2D2A Promoter

Contact Info

Product

Resources

About