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

Program for Undiagnosed Rare Diseases (UD-PrOZA), Levi Hoste, Lisa Roels, Marieke De Bruyne, Elfride De Baere, Jo Van Dorpe, Amélie Dendooven, Anne Sieben, Gillian I Rice, Tessa Kerre, Rudi Beyaert, Carolina Uggenti, Yanick J Crow, Simon J Tavernier, Jonathan Maelfait, Filomeen Haerynck*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output


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.

We performed a clinical, genetic, and immunological workup of 3 unrelated patients with uncharacterized AGS.

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.

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.

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.
Original languageEnglish
Number of pages13
JournalJournal of Clinical Immunology
Early online date23 Mar 2022
Publication statusE-pub ahead of print - 23 Mar 2022

Keywords / Materials (for Non-textual outputs)

  • Aicardi-Goutières syndrome
  • AGS
  • type I interferon
  • IFN-α
  • STAT phosphorylation
  • cGAS
  • U7 snRNP
  • small nuclear RNA
  • RNU7-1


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