title: When less is more: primary immunodeficiency with an autoinflammatory kick.
abstract: OBJECTIVE
  Next-generation sequencing is revolutionizing the molecular taxonomy of human disease. Recent studies of patients with unexplained autoinflammatory disorders reveal germline genetic mutations that target important regulators of innate immunity.
  
  
  RESULTS
  Whole-exome analyses of previously undiagnosed patients have catalyzed the recognition of two new disease genes. First, a phenotypic spectrum, including livedo racemosa, fever with early-onset stroke, polyarteritis nodosa, and Sneddon syndrome, is caused by loss-of-function mutations in cat eye syndrome chromosome region, candidate 1 (CECR1), encoding adenosine deaminase 2. Adenosine deaminase 2 is a secreted protein expressed primarily in myeloid cells, and a regulator of macrophage differentiation and endothelial development. Disease-associated mutations impair anti-inflammatory M2 macrophage differentiation. Second, patients presenting with cold-induced urticaria, granulomatous rash, autoantibodies, and common variable immunodeficiency, or with blistering skin lesions, bronchiolitis, enterocolitis, ocular inflammation, and mild immunodeficiency harbor distinct mutations in phospholipase Cγ₂, encoding a signaling molecule expressed in natural killer cells, mast cells, and B lymphocytes. These mutations inhibit the function of a phospholipase Cγ₂ autoinhibitory domain, causing increased or constitutive signaling.
  
  
  CONCLUSIONS
  These findings underscore the power of next-generation sequencing, demonstrating how the primary deficiency of key molecular regulators or even regulatory motifs may lead to autoinflammation, and suggesting a possible role for cat eye syndrome chromosome region, candidate 1 and phospholipase Cγ₂ in common diseases.
authors.affiliation: Inflammatory Disease Section, Intramural Research Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Giannelou
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017074:Common Variable Immunodeficiency / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000473:pathology; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D009154:Mutation; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D051966:Phospholipase C gamma; C408373:ADA2 protein, human; D000243:Adenosine Deaminase