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Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2 , associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans. Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.

Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi–Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1 , which encode components of the replication-dependent histone pre-mRNA–processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS–stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA. Mutations in LSM11 and RNU7-1 , which encode components of the replication-dependent histone pre-mRNA–processing complex, cause an autoinflammatory syndrome due to enhanced interferon signaling mediated by the cGAS–STING pathway, showing an essential role for nuclear histones in suppressing the immunogenicity of self-DNA.

Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A; yet the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in the Cri-du-Chat syndrome, as an SRGAP2 effector. We demonstrate that CTNND2 slows down synaptic maturation and promotes neuronal homeostasis. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in the synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C enhances CTNND2 synaptic accumulation in human neurons. Our findings reveal that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans, and link human-specific and ID genes at the synapse.

Bioenergetic metabolism is a key regulator of cellular function and signaling activity but the exact roles of nutrient utilization and energy production in embryonic development remain unknown. Here we investigated the metabolic pathways and deciphered the role of carbon metabolism required for the development of neural crest cells (NCC), a migratory stem cell population of the vertebrate embryo. We uncovered that glucose oxidation constitutes the prominent metabolic signature of trunk NCC and supports their delamination, migration, and proliferation. Additionally, we found that glycolysis, mitochondrial respiration and the pentose phosphate pathway are all mobilized downstream of glucose uptake. These metabolic pathways do not support specific cellular processes but cooperate and are integrated to accomplish epithelium-to-mesenchyme transition, adhesion, locomotion and proliferation. Moreover, using different nutrient supplies (glucose vs. pyruvate) we show that glucose is crucial to modulate NCC migration and adaptation to environmental stiffness, control NCC stemness and drive their fate decisions through regulation of specific gene expression. Our data establish that NCC development is instructed by metabolic cues that mobilize defined metabolic pathways cooperating together in response to nutrient availability. Here we show that neural crest cell migration and fate decisions rely primarily on glucose oxidation for energy production and mobilize multiple cooperating metabolic pathways for their biosynthetic needs and execution of gene programs.