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.
AGS
Aicardi-Goutières syndrome
IFN-α
RNU7-1
STAT phosphorylation
Small nuclear RNA
Type I interferon
U7 snRNP
cGAS
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
06
10
2021
accepted:
07
01
2022
pubmed:
24
3
2022
medline:
27
8
2022
entrez:
23
3
2022
Statut:
ppublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 35320431
doi: 10.1007/s10875-022-01209-5
pii: 10.1007/s10875-022-01209-5
pmc: PMC9402729
doi:
Substances chimiques
CXCL10 protein, human
0
Chemokine CXCL10
0
Histones
0
Lsm11 protein, human
0
RNA Precursors
0
RNA, Small Nuclear
0
RNA-Binding Proteins
0
U7 small nuclear RNA
0
RNA
63231-63-0
Interferons
9008-11-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
962-974Investigateurs
Steven Callens
(S)
Bart Dermaut
(B)
Wim Terryn
(W)
Nika Schuermans
(N)
Bruce Poppe
(B)
Informations de copyright
© 2022. The Author(s).
Références
McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A. Type I interferons in infectious disease. Nat Rev Immunol. 2015;15:87–103.
doi: 10.1038/nri3787
Aicardi J, Goutières F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984;15:49–54.
doi: 10.1002/ana.410150109
Livingston JH, Crow YJ. Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières syndrome and beyond. Neuropediatrics. 2016;47:355–60.
doi: 10.1055/s-0036-1592307
Rice GI, Forte GM, Szynkiewicz M, et al. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol. 2013;12:1159–69.
doi: 10.1016/S1474-4422(13)70258-8
La Piana R, Uggetti C, Roncarolo F, et al. Neuroradiologic patterns and novel imaging findings in Aicardi-Goutières syndrome. Neurology. 2016;86:28–35.
doi: 10.1212/WNL.0000000000002228
Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15:429–40.
doi: 10.1038/nri3850
Uggenti C, Lepelley A, Depp M, et al. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. Nat Genet. 2020;52:1364–72.
doi: 10.1038/s41588-020-00737-3
Vandeweyer G, Van Laer L, Loeys B, Van den Bulcke T, Kooy RF. VariantDB: a flexible annotation and filtering portal for next generation sequencing data. Genome Med. 2014;6:74.
doi: 10.1186/s13073-014-0074-6
Kolev NG, Steitz JA. In vivo assembly of functional U7 snRNP requires RNA backbone flexibility within the Sm-binding site. Nat Struct Mol Biol. 2006;13:347–53.
doi: 10.1038/nsmb1075
Gruber AR, Lorenz R, Bernhart SH, Neuböck R, Hofacker IL. The Vienna RNA websuite. Nucleic Acids Res. 2008;36:W70–4.
doi: 10.1093/nar/gkn188
Molnarfi N, Hyka-Nouspikel N, Gruaz L, Dayer JM, Burger D. The production of IL-1 receptor antagonist in IFN-beta-stimulated human monocytes depends on the activation of phosphatidylinositol 3-kinase but not of STAT1. J Immunol. 2005;174:2974–80.
doi: 10.4049/jimmunol.174.5.2974
Duncan CJA, Thompson BJ, Chen R, et al. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Sci Immunol. 2019;4.
Marzluff WF, Wagner EJ, Duronio RJ. Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat Rev Genet. 2008;9:843–54.
doi: 10.1038/nrg2438
Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.
doi: 10.1038/s41586-020-2308-7
Michalski S, de Oliveira Mann CC, Stafford CA, et al. Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature. 2020;587:678–82.
doi: 10.1038/s41586-020-2748-0
Volkman HE, Cambier S, Gray EE, Stetson DB. Tight nuclear tethering of cGAS is essential for preventing autoreactivity. Elife. 2019;8.
Du M, Chen ZJ. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science. 2018;361:704–9.
doi: 10.1126/science.aat1022
de Oliveira Mann CC, Hopfner KP. Nuclear cGAS: guard or prisoner. EMBO J. 2021;40:e108293.
doi: 10.15252/embj.2021108293
Lodi L, Melki I, Bondet V, et al. Differential expression of interferon-alpha protein provides clues to tissue specificity across type I interferonopathies. J Clin Immunol. 2021;41:603–9.
doi: 10.1007/s10875-020-00952-x
van Heteren JT, Rozenberg F, Aronica E, Troost D, Lebon P, Kuijpers TW. Astrocytes produce interferon-alpha and CXCL10, but not IL-6 or CXCL8, in Aicardi-Goutières syndrome. Glia. 2008;56:568–78.
doi: 10.1002/glia.20639
Arimoto KI, Löchte S, Stoner SA, et al. STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling. Nat Struct Mol Biol. 2017;24:279–89.
doi: 10.1038/nsmb.3378
Duncan CJA, Hambleton S. Human disease phenotypes associated with loss and gain of function mutations in STAT2: viral susceptibility and type I interferonopathy. J Clin Immunol. 2021;41:1446–56.
doi: 10.1007/s10875-021-01118-z
Ho J, Pelzel C, Begitt A, et al. STAT2 is a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways. PLoS Biol. 2016;14:e2000117.
doi: 10.1371/journal.pbio.2000117
Löchte S, Waichman S, Beutel O, You C, Piehler J. Live cell micropatterning reveals the dynamics of signaling complexes at the plasma membrane. J Cell Biol. 2014;207:407–18.
doi: 10.1083/jcb.201406032
Crow YJ, Chase DS, Lowenstein Schmidt J, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015;167A:296–312.
doi: 10.1002/ajmg.a.36887
Skrajna A, Yang XC, Bucholc K, et al. U7 snRNP is recruited to histone pre-mRNA in a FLASH-dependent manner by two separate regions of the stem-loop binding protein. RNA. 2017;23:938–51.
doi: 10.1261/rna.060806.117