A functional single nucleotide polymorphism, 1858C4T, in the PTPN22 gene, encoding a tyrosine phosphatase, has been reported to be associated with type I diabetes and some other autoimmune diseases. To further investigate whether this polymorphism may be a general susceptibility factor for autoimmunity, we performed an association study in five different autoimmune diseases, three previously not tested. We found an association with juvenile idiopathic arthritis (OR ¼ 1.41; P ¼ 0.04), not previously reported, and a tendency for an association with coeliac disease (OR ¼ 1.35; P ¼ 0.08). In primary sclerosing cholangitis, no association was observed (OR ¼ 0.95; P ¼ 0.8). Furthermore, we confirmed the increased risk in rheumatoid arthritis (OR ¼ 1.58; P ¼ 0.001), but could not find support for an association with systemic lupus erythematosus (OR ¼ 0.94; P ¼ 0.8). Altogether, we have provided further evidence of an association between autoimmune diseases and the 1858C4T polymorphism in PTPN22.
STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.
The IFN pathway gene, IRF5, is a common susceptibility factor for several rheumatic and autoimmune diseases, and risk variants are correlated with expression of alternative IRF5 transcripts in thymus implying a regulatory role.
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