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Background Aicardi-Goutières syndrome (AGS) is a type I interferonopathy usually characterized by early-onset neurologic regression. Biallelic mutations in  LSM11  and  RNU7-1 , components of the U7 small nuclear ribonucleoprotein (snRNP) complex, have been identified in a limited number of genetically unexplained AGS cases. Impairment of U7 snRNP function results in misprocessing of replication-dependent histone (RDH) pre-mRNA and disturbance of histone occupancy of nuclear DNA, ultimately driving cGAS-dependent type I interferon (IFN-I) release. Objective We performed a clinical, genetic, and immunological workup of 3 unrelated patients with uncharacterized AGS. Methods Whole exome sequencing (WES) and targeted Sanger sequencing of  RNU7-1  were performed. Primary fibroblasts were used for mechanistic studies. IFN-I signature and STAT1/2 phosphorylation were assessed in peripheral blood. Cytokines were profiled on serum and cerebrospinal fluid (CSF). Histopathology was examined on brain and kidney tissue. Results Sequencing revealed compound heterozygous  RNU7-1  mutations, resulting in impaired RDH pre-mRNA processing. The 3′ stem-loop mutations reduced stability of the secondary U7 snRNA structure. A discrete IFN-I signature in peripheral blood was paralleled by MCP-1 (CCL2) and CXCL10 upregulation in CSF. Histopathological analysis of the kidney showed thrombotic microangiopathy. We observed dysregulated STAT phosphorylation upon cytokine stimulation. Clinical overview of all reported patients with  RNU7-1 -related disease revealed high mortality and high incidence of organ involvement compared to other AGS genotypes. Conclusions Targeted  RNU7-1  sequencing is recommended in genetically unexplained AGS cases. CSF cytokine profiling represents an additional diagnostic tool to identify aberrant IFN-I signaling. Clinical follow-up of  RNU7-1 -mutated patients should include screening for severe end-organ involvement including liver disease and nephropathy.

journal of clinical immunology

Mutations in RNU7-1 Weaken Secondary RNA Structure, Induce MCP-1 and CXCL10 in CSF, and Result in Aicardi-Goutières Syndrome with Severe End-Organ Involvement