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Post-viral syndromes
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Anusha K. Yeshokumar, Eliza Gordon-Lipkin, Brenda Banwell
No single infectious agent has been implicated in ANE, leading to the hypothesis that host factors that determine how an individual’s immune system responds to infection may come into play. Further, identification of a gene linked to ANE may point to clues that underlie the pathogenesis of this disease. Thus far, it is unclear how the mutation in the protein produced from RANBP2 directly results in the clinical phenotype. Hypotheses exists that this gene may be linked to energy metabolism and mitochondrial function or that it may be linked to inappropriate cytokine response to infection [79,80].
Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
Nucleoporins are divided into two categories—those that display degenerate GLFG or XFXFG amino acid repeats indicative of O-linked glycosyl groups, and those that do not display this motif. Several proteins are identified with the cytoplasmic ring and fibrils, as shown in Figure 4 (91). CAN/Nup214/p250 binds WGA, indicative of the presence of the XFXFG repeat, while Nupl80 and Tpr/p268 have neither characteristic (Table 2). It has not yet been determined what roles these proteins play in nucleocytoplasmic transport. The peripheral locations of the proteins suggest their participation in binding events that lead toward the NPC, although it is shown that antibodies to Nupl80 do not inhibit protein transport (106). Recently the association between the NPC and nucleotide exhange proteins was localized to the cytoplasmic fibrils and confirmed by the identification of RanBP2, a Ran/TC4-binding protein (91). The active state of the protein, Ran-GTP is preferentially bound, and hydrolysis to Ran-GDP facilitates its release from the nucleoporin. RanBP2 is also O-linked glycosylated and displays 8 Zn2+ fingers, the function of which is unknown (91). Future studies regarding the components of the cytoplasmic fibril will verify the mechanism by which the nuclear transport substrate is concentrated at the NPC, a role that has long been suggested but only recently established by the characterization of NUP159. This yeast protein is localized to the cytoplasmic face of the NPC and has demonstrated binding to receptors that mediate protein nuclear import (refer to the section on Nuclear Localization Sequence Receptors).
Pathogenesis and Management of Acute Necrotizing Encephalopathy
Published in Expert Review of Neurotherapeutics, 2023
Ningxiang Qin, Jing Wang, Xi Peng, Liang Wang
In the last decade, the majority of research efforts have been directed toward understanding the mechanisms associated with mutations in the RANBP2 gene. ANE was first proposed and named by Mizuguchi et al. in 1995 [1]. In 2003, Neilson et al. discovered a multigenerational ANE family that was later identified as being caused by a RANBP2 gene mutation. To distinguish this type from the previously proposed sporadic ANE, it was named ANE1 [35]. Diagnosis of ANE1 is primarily based on Neilson’s 2003 diagnostic criteria, which include typical radiological findings, positive family history, and a confirmed RANBP2 missense mutation [36]. Compared to sporadic ANE, ANE1 exhibits an autosomal incomplete dominant inheritance pattern and has a higher recurrence rate. Approximately half of the patients with ANE1 have one or more episodes of ANE, while the other half are asymptomatic carriers [37]. Thus, ANE1 should also be considered for patients with their first onset of ANE. Neilson et al. found that ANE1 penetrance was related to differences in environmental triggers associated with the onset and individual differences in immune system components. ANE displays an intriguing inconsistency in its occurrence and manifestation, even in monozygotic twins with identical RANBP2 latent mutations, providing further evidence of the incomplete dominant inheritance characteristics of ANE [31]. Infections with various pathogens are frequently the cause of ANE [38]. Several RanBP2 gene mutations have been reported, including threonine to methionine mutations (T585M), T653I, I656V, T681C, and Lys1665Glu, with T585M accounting for the majority. RANBP2 is located on the cytoplasmic surface of the nuclear pore and is involved in the unpacking, modification, and recycling of proteins entering or leaving the nucleus and is essential for regulating glycolysis [25,39]. A missense mutation in RANBP2 can disrupt nuclear-cytoplasmic transport, gene expression regulation, mitochondrial function, and immune response, among other functions [31]. When faced with acute infections, failure of the nuclear pore of RANBP2 can lead to energy collapse, disruption of intracellular mitochondrial transport or energy production, lipid peroxidation, and changes in immune signaling [40]. Current research has identified various mutations in the RanBP2 gene, such as threonine-to-methionine substitution at position 585 (T585M), T653I, I656V, T681C, and Lys1665Glu. Notably, T585M is the most frequently observed mutation [25]. Targeting different mutation sites can provide new insights into treatment approaches and pathogenic mechanisms.