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

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.

GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

“…gnomAD does not annotate healthy individuals harboring homozygous truncating GTF3A mutations (26). A similar inheritance pattern has been observed for other genetic diseases with biallelic mutations targeting essential housekeeping genes (33)(34)(35). The proband developed HSE, whereas his sibling carrying the same biallelic mutations did not.…”

SMN controls neuromuscular junction integrity through U7 snRNP

“…These findings have potential translational implications; further mechanistic dissection of the SMN-dependent pathway highlighted here may provide therapeutic entry points to counteract NMJ deficits in SMA and other diseases. Recently, mutations in the LSM11 and U7 ( RNU7 ) genes have been linked to Aicardi-Goutières syndrome (AGS) ( Naesens et al, 2022 ; Uggenti et al, 2020 ), and defective Agrin expression could contribute to some of the clinical features of AGS involving muscle dysfunction. The dysregulation of this pathway could also participate in the NMJ pathology of other neurodegenerative diseases like ALS, for which there is evidence of interference with SMN function ( Sun et al, 2015 ; Yamazaki et al, 2012 ) and histone mRNA expression ( Amlie-Wolf et al, 2015 ; Gadgil et al, 2021 ; Igaz et al, 2011 ), as well as mitigation of muscle denervation by enhanced Agrin signaling in mouse models ( Cantor et al, 2018 ; Pérez-García and Burden, 2012 ).…”

Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders

“…Variants in RNU7-1 were confirmed using Sanger sequencing as described in a study in 2022. 14 The variants in SNORD118 were detected using Sanger sequencing. Primer sequences are available on request.…”

“…20 In a 20-year-old male patient (eTable 2, links.lww.com/NXG/ A602; p.143) with a clinical diagnosis of Aicardi-Goutieres syndrome presenting with severe intellectual disability, periventricular leukomalacia, and cerebral calcifications, analysis of the leukoencephalopathy gene panel initially did not result in a diagnosis. After RNU7-1, a gene encoding a component of the replication-dependent histone pre-mRNA-processing complex, was described as a novel cause of Aicardi-Goutieres syndrome 9, 14,21 we reanalyzed the data and found compound heterozygosity for 2 pathogenic variants in RNU7- We highlight the identification of a novel missense variant in the APP gene (c.2092A>G, p.[Asn698Asp]), encoding the amyloid beta-A4 precursor protein, in a 75-year-old female patient (p.98) with recurrent stroke and diffuse leukoencephalopathy consistent with cerebral small vessel disease (CSVD) (Figure 2, A and B). Family history was positive with an older brother who suffered from recurrent stroke with periventricular leukodystrophy and multiple lacunar infarcts associated with rapid cognitive decline (Figure 2C).…”