The molecular taxonomy of human illness is being transformed by next-generation sequencing. Recent research on patients with unexplained autoinflammatory diseases has revealed germline genetic abnormalities that target key innate immunity regulators. The identification of two novel disease genes has been aided by whole-exome studies of previously undiagnosed individuals. First, loss-of-function mutations in the cat eye syndrome chromosomal region, candidate 1 (CECR1), encoding adenosine deaminase 2, induce a clinical range that includes livedo racemosa, fever with early-onset stroke, polyarteritis nodosa, and Sneddon syndrome. Myeloid cells produce Adenosine DEAMINASE 2, which is a secreted protein that regulates macrophage differentiation and endothelium development. M2 macrophage differentiation is impaired by disease-associated mutations. A separate group of patients presenting with cold-induced skin lesions and autoantibodies as well as common variable immunodeficiency have mutations in phospholipase C2, which encodes a signaling molecule expressed in natural killer cells (NK) cells, mast cells (M) cells, and B lymphocytes (B lymphocyte). A phospholipase C2 autoinhibitory domain is inhibited, resulting in an enhanced or constitutive signaling response.
A fundamental lack of critical molecular regulators or even regulatory motifs may lead to autoinflammation, as demonstrated by these findings. They also point to the function of cat eye syndrome candidate 1 and phospholipase C2 in common illnesses.
