Autoimmunity and apoptosis: The Crohn's connection

Complex genetic disorders have begun to yield to sequential positional cloning initiatives. Both in humans and in mice, given that multiple susceptibility loci can be established, it is generally possible to dissect phenotypes one gene at a time. The first step has been taken in Crohn's disease. But even simple genetic disorders pose problems of interpretation once they are solved by positional methods. How does huntingtin create its phenotype? How do mutations of superoxide dismutase create amyotrophic lateral sclerosis? How do mutations of NRAMP enhance susceptibility to mycobacterial infection? When numerous mutations are responsible for a phenotype, the riddle is more challenging still. NOD2 has become the eighth protein known to have strong ties to cell death pathways and to autoimmunity. Mutations of NOD2 are responsible for a discrete autoimmune disease. But as to how they create the phenotype, much remains to be learned.