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

J Clin Immunol. 2022 Jul;42(5):962-974. doi: 10.1007/s10875-022-01209-5. Epub 2022 Mar 23.

Abstract

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.

Keywords: AGS; Aicardi-Goutières syndrome; IFN-α; RNU7-1; STAT phosphorylation; Small nuclear RNA; Type I interferon; U7 snRNP; cGAS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases of the Nervous System* / diagnosis
  • Autoimmune Diseases of the Nervous System* / genetics
  • Chemokine CXCL10 / genetics
  • Histones
  • Humans
  • Interferons
  • Mutation
  • Nervous System Malformations* / diagnosis
  • Nervous System Malformations* / genetics
  • RNA
  • RNA Precursors / chemistry
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA, Small Nuclear / genetics*
  • RNA-Binding Proteins / genetics

Substances

  • CXCL10 protein, human
  • Chemokine CXCL10
  • Histones
  • Lsm11 protein, human
  • RNA Precursors
  • RNA, Small Nuclear
  • RNA-Binding Proteins
  • U7 small nuclear RNA
  • RNA
  • Interferons

Supplementary concepts

  • Aicardi-Goutieres syndrome