• Maya Saleh, John P Vaillancourt, Rona K Graham, Matthew Huyck, Srinivasa M Srinivasula, Emad S Alnemri, Martin H Steinberg, Vikki Nolan, Clinton T Baldwin, Richard S Hotchkiss, Timothy G Buchman, Barbara A Zehnbauer, Michael R Hayden, Lindsay A Farrer, Sophie Roy, and Donald W Nicholson.
• Department of Biochemistry, Molecular Biology and Pharmacology, Merck Frosst Centre for Therapeutic Research, Montreal, Quebec H9H 3L1, Canada.
• Nature. 2004 May 6;429(6987):75-9.

AbstractCaspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.

40 keywords...

hide…