Published in:
Open Access
23-03-2022 | Cytokines | Original Article
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
Authors:
Leslie Naesens, Josephine Nemegeer, Filip Roelens, Lore Vallaeys, Marije Meuwissen, Katrien Janssens, Patrick Verloo, Benson Ogunjimi, Dimitri Hemelsoet, 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, Program for Undiagnosed Rare Diseases (UD-PrOZA)
Published in:
Journal of Clinical Immunology
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Issue 5/2022
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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.