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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

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Abstract
Background Aicardi-Goutieres 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
Immunology, Immunology and Allergy, Aicardi-Goutieres syndrome, AGS, Type I interferon, IFN-alpha, STAT phosphorylation, cGAS, U7 snRNP, Small nuclear RNA, RNU7-1, PRE-MESSENGER-RNA, I INTERFERON, U7 SNRNP, RNASEH2A, SAMHD1, TREX1, ADAR

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MLA
Naesens, Leslie, et al. “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.” JOURNAL OF CLINICAL IMMUNOLOGY, 2022, doi:10.1007/s10875-022-01209-5.
APA
Naesens, L., Nemegeer, J., Roelens, F., Vallaeys, L., Meuwissen, M., Janssens, K., … Program for Undiagnosed Rare Diseases (UD-PrOZA), [missing]. (2022). 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. JOURNAL OF CLINICAL IMMUNOLOGY. https://doi.org/10.1007/s10875-022-01209-5
Chicago author-date
Naesens, Leslie, Josephine Nemegeer, Filip Roelens, Lore Vallaeys, Marije Meuwissen, Katrien Janssens, Patrick Verloo, et al. 2022. “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.” JOURNAL OF CLINICAL IMMUNOLOGY. https://doi.org/10.1007/s10875-022-01209-5.
Chicago author-date (all authors)
Naesens, Leslie, 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 Tavernier, Jonathan Maelfait, Filomeen Haerynck, and [missing] Program for Undiagnosed Rare Diseases (UD-PrOZA). 2022. “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.” JOURNAL OF CLINICAL IMMUNOLOGY. doi:10.1007/s10875-022-01209-5.
Vancouver
1.
Naesens L, Nemegeer J, Roelens F, Vallaeys L, Meuwissen M, Janssens K, et al. 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. JOURNAL OF CLINICAL IMMUNOLOGY. 2022;
IEEE
[1]
L. Naesens et al., “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,” JOURNAL OF CLINICAL IMMUNOLOGY, 2022.
@article{8747264,
  abstract     = {{Background Aicardi-Goutieres 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.}},
  author       = {{Naesens, Leslie and Nemegeer, Josephine and Roelens, Filip and Vallaeys, Lore and Meuwissen, Marije and Janssens, Katrien and Verloo, Patrick and Ogunjimi, Benson and Hemelsoet, Dimitri and Hoste, Levi and Roels, Lisa and De Bruyne, Marieke and De Baere, Elfride and Van Dorpe, Jo and Dendooven, Amélie and Sieben, Anne and Rice, Gillian I. and Kerre, Tessa and Beyaert, Rudi and Uggenti, Carolina and Crow, Yanick J. and Tavernier, Simon and Maelfait, Jonathan and Haerynck, Filomeen and Program for Undiagnosed Rare Diseases (UD-PrOZA), [missing]}},
  issn         = {{0271-9142}},
  journal      = {{JOURNAL OF CLINICAL IMMUNOLOGY}},
  keywords     = {{Immunology,Immunology and Allergy,Aicardi-Goutieres syndrome,AGS,Type I interferon,IFN-alpha,STAT phosphorylation,cGAS,U7 snRNP,Small nuclear RNA,RNU7-1,PRE-MESSENGER-RNA,I INTERFERON,U7 SNRNP,RNASEH2A,SAMHD1,TREX1,ADAR}},
  language     = {{eng}},
  pages        = {{13}},
  title        = {{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}},
  url          = {{http://dx.doi.org/10.1007/s10875-022-01209-5}},
  year         = {{2022}},
}

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