When less is more

Abstract

Purpose of reviewNext-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.Recent findingsWhole-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.SummaryThese 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.

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder

“…Replacement by larger residues, such as Y, F, P, D, and E leads to increased basal activities of PLCγ 2 in intact cells, irrespective of the polarity of the side chain. Phosphorylation of Y707 in the mutant S707Y, suggested earlier to be a potential cause of PLCγ 2 activation [ 3 , 24 ] is an unlikely reason of PLCγ 2 activation, since the mutant S707F also displayed enhanced activity ( cf. Figure 1B ).…”

“…Alternatively, autoinhibition of the catalytic core may be more complex and rely on mechanisms in addition to cSH2-catalytic-core-interaction. In any case, the functional differences between the PLAID and the APLAID PLCγ 2 mutants shown here provides a conceptual framework for the understanding of the functional differences observed in intact immune cells such as B cells [ 3 , 24 ], and may explain activation of the NLRP3 inflammasome in peripheral blood mononuclear cells of APLAID patients [ 14 ] Interestingly, the NLRP3 inflammasome plays an important role in the pathogenesis of not only relatively rare disorders such as cryopyrin-associated periodic syndromes (CAPS), but also more common diseases such as gout, type 2 diabetes mellitus, artherosclerosis, and Alzheimer's disease (referenced in [ 14 ]. This raises the possibility that alterations in PLCγ 2 activity may be involved in these diseases as well.…”

ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans

“…This can affect the interaction of the autoinhibitory and catalytic regions, consequently reducing the autoinhibition of PLCγ2. Thus, PLCG2 _rs72824905-G is expected to increase the PLCγ2 signaling activity, which may induce activation of inflammation and innate immunity [ 5 , 6 ].…”

“…PLCG2 encodes phosphoinositide-specific phospholipase C family protein PLCɣ2, which, upon extracellular ligand stimulation of receptor tyrosine kinase, is activated by recruitment to the cell membrane and phosphorylation [ 5 , 6 ]. Consequently, PLCɣ2 hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP 2 ) and diacylglycerol (DAG), which increases calcium (Ca 2+ ) influx and extracellular signal-regulated kinase (ERK) phosphorylation, thereby inducing cellular activation in settings including inflammation and innate immunity [ 5 , 6 ]. The murine Plcγ2 Ali5 gain-of-function point mutation in the catalytic domain of this protein near its auto-inhibitory domain leads to enhanced Ca 2+ influx in B-cells and expansion of innate inflammatory cells, resulting in autoimmunity and inflammation in this model [ 7 ].…”

Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases

“…For examples, the patients with mutations in the pyrimidine synthesis gene UMPS and the purine synthesis gene PNP have T cell deficiencies 24 25 , and patients with mutations in the purine synthesis gene ADA1 have deficiencies in both T cells and B cells 26 . Finally, mutations in ADA2 , another gene involved in purine metabolism, caused mild lymphopenia in humans and reduced neutrophil development in the zebrafish 27 28 . Taken together, these data strongly suggest PRPS1-related nucleotide synthesis is an important factor in leukocyte homeostasis and infection prevention.…”