A point mutation of the ZAP70 gene as the primary cause of SKG arthritis

Cure Arthritis Naturally

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The primary cause of SKG arthritis is a genetic abnormality inherited in an autosomal recessive fashion with nearly 100% penetrance of the trait in homozygotes raised in our conventional environment. Linkage analysis between the development of macroscopically evident arthritis and the homozygosity of chromosome-specific microsatellite markers maps the skg locus to the centromeric portion of chromosome 1 with the lod score of the locus as infinite. Construction of a high-resolution genetic map of the skg region, screening of yeast or bacterial artificial chromosome libraries for clones that cover the putative skg locus, and sequencing of such clones revealed a homozygous G-to-T substitution at nucleotide 489 in the SKG ZAP-70 gene, which alters codon163 from tryptophan to cysteine (W163C) (Fig. 1). The

TCR-CD3 complex

TCR-CD3 complex

Skg Mice Sh2 Sh2c Zap

Figure 1

The ZAP-70 gene mutation and the mechanism of arthritis development in SKG mice.

position of the mutation corresponds to the initial amino acid residue of the C-ter-minal SH2 (SH2C) domain of ZAP-70 [16]. The revealed ZAP-70W163C missense mutation is primarily responsible for SKG arthritis because ZAP-70-skg/- mice, made by mating ZAP-70-deficient (ZAP-70-/-) mice with SKG (ZAP-70-skg/skg) mice, develop arthritis whereas ZAP-70-skg/+ mice do not. In addition, T-cell-spe-cific transgenic expression of the normal human ZAP-70 gene under the lck proximal promoter completely inhibits the development of arthritis in SKG mice where as non-Tg littermates develop arthritis at 100% incidence. Thus, the ZAP-70W163C alteration is not a mere polymorphism but the causative mutation of autoimmune arthritis in SKG mice.

As the consequence of the ZAP-70W163C mutation, the tyrosine-phosphorylation status of major signal transduction molecules, including ZAP-70, TCR-Z, LAT (linker for the activation of T-cells) and PLC-y1, is extremely low in thymocytes and T-cells [17-19]. Calcium mobilization, one of the earliest events induced by TCR stimulation, is also greatly impaired in SKG thymocytes and T-cells presumably due to the reduced phosphorylation of PLC-y1. Immunoprecipitation of ZAP-70 from stimulated SKG thymocytes and T-cells fail to co-precipitate tyrosine-phosphorylat-ed p21 and p23 isoforms of TCR-Z, indicating a defective interaction between ZAP-70 and TCR-Z. SKG T-cells show no enhancement of the expression of Syk, another protein tyrosine kinase which might compensate the role of ZAP-70 in T-cells (T. Takahashi, unpublished data). Taken together, the ZAP-70W163C mutation may impair the recruitment and association of ZAP-70 to tyrosine-phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) of TCR-Z and CD3 chains, thereby altering signal transduction through ZAP-70. Analysis of downstream MAP kinase activation in SKG thymocytes upon in vitro TCR stimulation shows that activation levels of ERK1/2 and p38 MAP kinases are less than 50% of control BALB/c thymocytes in every activation phase [20]. The kinetics of activation of both p54 and p46 JNK isoforms is also delayed in SKG thymocytes compared with BALB/c thymocytes. Thus, SKG thymocytes exhibit hypo-activation of three families of MAPKs upon TCR stimulation [12]. The attenuated ERK and P38/JNK pathways would impair positive and negative selection, respectively, of T-cells in SKG mice (see below) [21].

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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