{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:04:16Z","timestamp":1791443056236,"version":"4.3.3"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Clin Immunol"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Aicardi-Gouti\u00e8res syndrome (AGS) is a type I interferonopathy usually characterized by early-onset neurologic regression. Biallelic mutations in\n                      <jats:italic>LSM11<\/jats:italic>\n                      and\n                      <jats:italic>RNU7-1<\/jats:italic>\n                      , 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We performed a clinical, genetic, and immunological workup of 3 unrelated patients with uncharacterized AGS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Whole exome sequencing (WES) and targeted Sanger sequencing of\n                      <jats:italic>RNU7-1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sequencing revealed compound heterozygous\n                      <jats:italic>RNU7-1<\/jats:italic>\n                      mutations, resulting in impaired RDH pre-mRNA processing. The 3\u2032 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\n                      <jats:italic>RNU7-1<\/jats:italic>\n                      -related disease revealed high mortality and high incidence of organ involvement compared to other AGS genotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Targeted\n                      <jats:italic>RNU7-1<\/jats:italic>\n                      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\n                      <jats:italic>RNU7-1<\/jats:italic>\n                      -mutated patients should include screening for severe end-organ involvement including liver disease and nephropathy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10875-022-01209-5","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T01:02:30Z","timestamp":1647997350000},"page":"962-974","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Mutations in RNU7-1 Weaken Secondary RNA Structure, Induce MCP-1 and CXCL10 in CSF, and Result in Aicardi-Gouti\u00e8res Syndrome with Severe End-Organ 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