A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase Cγ2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency

Whole-exome sequencing was performed in a family affected by dominantly inherited inflammatory disease characterized by recurrent blistering skin lesions, bronchiolitis, arthralgia, ocular inflammation, enterocolitis, absence of autoantibodies, and mild immunodeficiency. Exome data from three samples, including the affected father and daughter and unaffected mother, were filtered for the exclusion of reported variants, along with benign variants, as determined by PolyPhen-2. A total of eight transcripts were identified as possible candidate genes. We confirmed a variant, c.2120C>A (p.Ser707Tyr), within PLCG2 as the only de novo variant that was present in two affected family members and not present in four unaffected members. PLCG2 encodes phospholipase Cγ2 (PLCγ2), an enzyme with a critical regulatory role in various immune and inflammatory pathways. The p.Ser707Tyr substitution is located in an autoinhibitory SH2 domain that is crucial for PLCγ2 activation. Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals’ leukocytes showed clearly enhanced PLCγ2 activity, suggesting increased intracellular signaling in the PLCγ2-mediated pathway. Recently, our laboratory identified in individuals with cold-induced urticaria and immune dysregulation PLCG2 exon-skipping mutations resulting in protein products with constitutive phospholipase activity but with reduced intracellular signaling at physiological temperatures. In contrast, the p.Ser707Tyr substitution in PLCγ2 causes a distinct inflammatory phenotype that is not provoked by cold temperatures and that has different end-organ involvement and increased intracellular signaling at physiological temperatures. Our results highlight the utility of exome-sequencing technology in finding causal mutations in nuclear families with dominantly inherited traits otherwise intractable by linkage analysis

Inevitable, yes, but desirable?

Barbara Santichhttp://editore.slowfood.com/editore/eng/slow.lass

Australian Aborigines

Barbara Santic

Food

Barbara Santic

Australian food innovations

In accordance with the chosen theme for the Convention, A Celebration and Exploration of Food Science and Technology, it is appropriate to review some of the significant advances in food science and technology that have been made in Australia - innovations that have been introduced over the past 200 years. My perspective is that of food historian rather than scientist or technologist, and is therefore rather broader, ranging from the agricultural beginnings of food to the final product on the diner's plate, and encompasses everything in between. This perspective is guided by the result rather than the science or technology used to produce it. It is also the perspective of gastronomy, which is what I teach at the University of Adelaid

Revenge, cannibalism and self-denial

Also published as journal article - Food and History, 2003; 1 (1):85-94Barbara Santichhttp://www.brepols.net/Pages/ShowProduct.aspx?prod_id=IS-9782503514697-