Статті в журналах: "RNF216"

1

Melnick, Ashley F., Yuen Gao, Jiali Liu, Deqiang Ding, Alicia Predom, Catherine Kelly, Rex A. Hess, and Chen Chen. "RNF216 is essential for spermatogenesis and male fertility†." Biology of Reproduction 100, no. 5 (January 15, 2019): 1132–34. http://dx.doi.org/10.1093/biolre/ioz006.

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Abstract Ring finger protein 216 (RNF216) belongs to the RING family of E3 ubiquitin ligases that are involved in cellular protein degradation. Mutations in human Rnf216 gene have been identified in Gordon Holmes syndrome, which is defined by ataxia, dementia, and hypogonadotropism. However, the gene function of Rnf216 in mammalian species remains unknown. Here, we show that targeted deletion of Rnf216 in mice results in disruption in spermatogenesis and male infertility. RNF216 is not required for female fertility. These findings reveal an essential function of RNF216 in spermatogenesis and male fertility and suggest a critical role for RNF216 in human gonadal development.

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2

Seenivasan, Ramkumar, Thomas Hermanns, Tamara Blyszcz, Michael Lammers, Gerrit J. K. Praefcke, and Kay Hofmann. "Mechanism and chain specificity of RNF216/TRIAD3, the ubiquitin ligase mutated in Gordon Holmes syndrome." Human Molecular Genetics 28, no. 17 (April 24, 2019): 2862–73. http://dx.doi.org/10.1093/hmg/ddz098.

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AbstractGordon Holmes syndrome (GDHS) is an adult-onset neurodegenerative disorder characterized by ataxia and hypogonadotropic hypogonadism. GDHS is caused by mutations in the gene encoding the RING-between-RING (RBR)-type ubiquitin ligase RNF216, also known as TRIAD3. The molecular pathology of GDHS is not understood, although RNF216 has been reported to modify several substrates with K48-linked ubiquitin chains, thereby targeting them for proteasomal degradation. We identified RNF216 in a bioinformatical screen for putative SUMO-targeted ubiquitin ligases and confirmed that a cluster of predicted SUMO-interaction motifs (SIMs) indeed recognizes SUMO2 chains without targeting them for ubiquitination. Surprisingly, purified RNF216 turned out to be a highly active ubiquitin ligase that exclusively forms K63-linked ubiquitin chains, suggesting that the previously reported increase of K48-linked chains after RNF216 overexpression is an indirect effect. The linkage-determining region of RNF216 was mapped to a narrow window encompassing the last two Zn-fingers of the RBR triad, including a short C-terminal extension. Neither the SIMs nor a newly discovered ubiquitin-binding domain in the central portion of RNF216 contributes to chain specificity. Both missense mutations reported in GDHS patients completely abrogate the ubiquitin ligase activity. For the R660C mutation, ligase activity could be restored by using a chemical ubiquitin loading protocol that circumvents the requirement for ubiquitin-conjugating (E2) enzymes. This result suggests Arg-660 to be required for the ubiquitin transfer from the E2 to the catalytic cysteine. Our findings necessitate a re-evaluation of the previously assumed degradative role of RNF216 and rather argue for a non-degradative K63 ubiquitination, potentially acting on SUMOylated substrates.

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3

Ganos, Christos, Joshua Hersheson, Matthew Adams, Kailash P. Bhatia, and Henry Houlden. "Syndromic associations and RNF216 mutations." Parkinsonism & Related Disorders 21, no. 11 (November 2015): 1389–90. http://dx.doi.org/10.1016/j.parkreldis.2015.09.010.

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4

Ganos, Christos, Joshua Hersheson, Matthew Adams, Kailash P. Bhatia, and Henry Houlden. "The 4H syndrome due to RNF216 mutation." Parkinsonism & Related Disorders 21, no. 9 (September 2015): 1122–23. http://dx.doi.org/10.1016/j.parkreldis.2015.07.012.

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5

Wolf, Nicole I., and Geneviève Bernard. "Mutations in RNF216 do not cause 4H syndrome." Parkinsonism & Related Disorders 21, no. 11 (November 2015): 1387–88. http://dx.doi.org/10.1016/j.parkreldis.2015.09.014.

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6

Xu, Congfeng, Kuan Feng, Xiaonan Zhao, Shiqian Huang, Yiji Cheng, Liu Qian, Yanan Wang, et al. "Regulation of autophagy by E3 ubiquitin ligase RNF216 through BECN1 ubiquitination." Autophagy 10, no. 12 (November 11, 2014): 2239–50. http://dx.doi.org/10.4161/15548627.2014.981792.

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7

Santens, P., T. Van Damme, W. Steyaert, A. Willaert, B. Sablonniere, A. De Paepe, P. J. Coucke, and B. Dermaut. "RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder." Neurology 84, no. 17 (April 3, 2015): 1760–66. http://dx.doi.org/10.1212/wnl.0000000000001521.

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8

Calandra, Cristian R., Yamile Mocarbel, Sebastian A. Vishnopolska, Vanessa Toneguzzo, Jaen Oliveri, Enrique Carlos Cazado, German Biagioli, Adrián G. Turjanksi, and Marcelo Marti. "Gordon Holmes Syndrome Caused by RNF216 Novel Mutation in 2 Argentinean Siblings." Movement Disorders Clinical Practice 6, no. 3 (January 16, 2019): 259–62. http://dx.doi.org/10.1002/mdc3.12721.

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9

Chen, Ke‐Liang, Gui‐Xian Zhao, He Wang, Lei Wei, Yu‐Yuan Huang, Shi‐Dong Chen, Bi‐Ying Lin, Qiang Dong, Mei Cui, and Jin‐Tai Yu. "A novel de novo RNF216 mutation associated with autosomal recessive Huntington‐like disorder." Annals of Clinical and Translational Neurology 7, no. 5 (May 2020): 860–64. http://dx.doi.org/10.1002/acn3.51047.

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10

Young, J., I. Abdennebi, F. Magnin, L. Maione, J. Bouligand, and I. Beau. "Mutations bialléliques de RNF216 dans l’hypogonadisme hypogonadotrophique avec ataxie cérébelleuse : conséquences fonctionnelles sur l’autophagie." Annales d'Endocrinologie 83, no. 5 (October 2022): 317. http://dx.doi.org/10.1016/j.ando.2022.07.108.

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11

Wang, Hui, Yanan Wang, Liu Qian, Xue Wang, Hailiang Gu, Xiaoqiang Dong, Shiqian Huang, et al. "RNF216 contributes to proliferation and migration of colorectal cancer via suppressing BECN1-dependent autophagy." Oncotarget 7, no. 32 (May 18, 2016): 51174–83. http://dx.doi.org/10.18632/oncotarget.9433.

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12

Chen, Tao, Jie Zhu, and Yu‐Hai Wang. "RNF216 mediates neuronal injury following experimental subarachnoid hemorrhage through the Arc/Arg3.1‐AMPAR pathway." FASEB Journal 34, no. 11 (September 12, 2020): 15080–92. http://dx.doi.org/10.1096/fj.201903151rrrr.

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13

Poulsen, Maria, Claudia Lukas, Jiri Lukas, Simon Bekker-Jensen, and Niels Mailand. "Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks." Journal of Cell Biology 197, no. 2 (April 9, 2012): 189–99. http://dx.doi.org/10.1083/jcb.201109100.

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Nonproteolytic ubiquitylation of chromatin surrounding deoxyribonucleic acid double-strand breaks (DSBs), mediated by the RNF8/RNF168 ubiquitin ligases, plays a key role in recruiting repair factors, including 53BP1 and BRCA1, to reestablish genome integrity. In this paper, we show that human RNF169, an uncharacterized E3 ubiquitin ligase paralogous to RNF168, accumulated in DSB repair foci through recognition of RNF168-catalyzed ubiquitylation products by its motif interacting with ubiquitin domain. Unexpectedly, RNF169 was dispensable for chromatin ubiquitylation and ubiquitin-dependent accumulation of repair factors at DSB sites. Instead, RNF169 functionally competed with 53BP1 and RAP80–BRCA1 for association with RNF168-modified chromatin independent of its catalytic activity, limiting the magnitude of their recruitment to DSB sites. By delaying accumulation of 53BP1 and RAP80 at damaged chromatin, RNF169 stimulated homologous recombination and restrained nonhomologous end joining, affecting cell survival after DSB infliction. Our results show that RNF169 functions in a noncanonical fashion to harness RNF168-mediated protein recruitment to DSB-containing chromatin, thereby contributing to regulation of DSB repair pathway utilization.

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14

Rothzerg, Emel, Jiake Xu, and David Wood. "Identification of Differentially Expressed Intronic Transcripts in Osteosarcoma." Non-Coding RNA 8, no. 6 (October 25, 2022): 73. http://dx.doi.org/10.3390/ncrna8060073.

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Over the past decade; the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed that they play a major role in the development of various diseases; including cancer. Intronic transcripts are one of the most fascinating lncRNAs that are located within intron regions of protein-coding genes, which have the advantage of encoding micropeptides. There have been several studies looking at intronic transcript expression profiles in cancer; but almost none in osteosarcoma. To overcome this problem; we have investigated differentially expressed intronic transcripts between osteosarcoma and normal bone tissues. The results highlighted that NRG1-IT1; FGF14-IT1; and HAO2-IT1 were downregulated; whereas ER3-IT1; SND1-IT1; ANKRD44-IT1; AGAP1-IT1; DIP2A-IT1; LMO7DN-IT1; SLIT2-IT1; RNF216-IT1; and TCF7L1-IT1 were upregulated in osteosarcoma tissues compared to normal bone tissues. Furthermore, we identified if the transcripts encode micropeptides and the transcripts’ locations in a cell.

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15

George, Arlene J., Bin Dong, Hannah Lail, Morgan Gomez, Yarely C. Hoffiz, Christopher B. Ware, Ning Fang, et al. "The E3 ubiquitin ligase RNF216/TRIAD3 is a key coordinator of the hypothalamic-pituitary-gonadal axis." iScience 25, no. 10 (October 2022): 105108. http://dx.doi.org/10.1016/j.isci.2022.105108.

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16

Chen, Ke-Liang, He Wang, Gui-Xian Zhao, Lei Wei, Yu-Yuan Huang, Shi-Dong Chen, Jian Sun, Qiang Dong, Mei Cui, and Jin-Tai Yu. "Whole-Exome Sequencing Identified a Novel Mutation in RNF216 in a Family with Gordon Holmes Syndrome." Journal of Molecular Neuroscience 72, no. 4 (January 28, 2022): 691–94. http://dx.doi.org/10.1007/s12031-021-01953-0.

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17

Cotton, Thomas R., Simon A. Cobbold, Jonathan P. Bernardini, Lachlan W. Richardson, Xiangyi S. Wang, and Bernhard C. Lechtenberg. "Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216." Molecular Cell 82, no. 3 (February 2022): 598–615. http://dx.doi.org/10.1016/j.molcel.2021.12.005.

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18

Husain, Nilofer, Qiang Yuan, Yi-Chun Yen, Olga Pletnikova, Dong Qianying Sally, Paul Worley, Zoë Bichler, and H. Shawn Je. "TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation." Aging Cell 16, no. 2 (December 20, 2016): 281–92. http://dx.doi.org/10.1111/acel.12551.

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19

Zhang, Chunfeng, Yang Yang, Kun Wang, Muhua Chen, Min Lu, Chenyu Hu, Xiaojuan Du, Baocai Xing, and Xiaofeng Liu. "The Systematic Analyses of RING Finger Gene Signature for Predicting the Prognosis of Patients with Hepatocellular Carcinoma." Journal of Oncology 2022 (September 26, 2022): 1–17. http://dx.doi.org/10.1155/2022/2466006.

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RING finger (RNF) proteins are frequently dysregulated in human malignancies and are tightly associated with tumorigenesis. However, the expression profiles of RNF genes in hepatocellular carcinoma (HCC) and their relations with prognosis remain undetermined. Here, we aimed at constructing a prognostic model according to RNF genes for forecasting the outcomes of HCC patients using the data from The Cancer Genome Atlas (TCGA) program. We collected HCC datasets to validate the values of our model in predicting prognosis of HCC patients from International Cancer Genome Consortium (ICGC) platform. Then, functional experiments were carried out to explore the roles of the representative RNF in HCC progression. A total of 107 differentially expressed RNFs were obtained between TCGA-HCC tumor and normal tissues. After comprehensive evaluation, a prognostic signature composed of 11 RNFs (RNF220, RNF25, TRIM25, BMI1, RNF216P1, RNF115, RNF2, TRAIP, RNF157, RNF145, and RNF19B) was constructed based on TCGA cohort. Then, the Kaplan-Meier (KM) curves and the receiver operating characteristic curve (ROC) were employed to evaluate predictive power of the prognostic model in testing cohort (TCGA) and validation cohort (ICGC). The KM and ROC curves illustrated the good predictive power in testing and validation cohort. The areas under the ROC curve are 0.77 and 0.76 in these two cohorts, respectively. Among the prognostic signature genes, BMI1 was selected as a representative for functional study. We found that BMI1 protein level was significantly upregulated in HCC tissues. Moreover, the inhibitor of BMI1, PTC-209, displayed an excellent anti-HCC effect in vitro. Enrichment analysis of BMI1 downstream targets showed that BMI1 might be involved in tumor immunotherapy. Together, our overall analyses revealed that the 11-RNFs prognostic signature might provide us latent chances for evaluating HCC prognosis and developing novel HCC therapy.

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20

Goitia, Veronica, Marcial Oquendo, and Robert Stratton. "Case of 7p22.1 Microduplication Detected by Whole Genome Microarray (REVEAL) in Workup of Child Diagnosed with Autism." Case Reports in Genetics 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/212436.

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Introduction. More than 60 cases of 7p22 duplications and deletions have been reported with over 16 of them occurring without concomitant chromosomal abnormalities.Patient and Methods. We report a 29-month-old male diagnosed with autism. Whole genome chromosome SNP microarray (REVEAL) demonstrated a 1.3 Mb interstitial duplication of 7p22.1 ->p22.1 arr 7p22.1 (5,436,367–6,762,394), the second smallest interstitial 7p duplication reported to date. This interval included 14 OMIM annotated genes (FBXL18, ACTB, FSCN1, RNF216, OCM, EIF2AK1, AIMP2, PMS2, CYTH3, RAC1, DAGLB, KDELR2, GRID2IP,and ZNF12).Results. Our patient presented features similar to previously reported cases with 7p22 duplication, including brachycephaly, prominent ears, cryptorchidism, speech delay, poor eye contact, and outburst of aggressive behavior with autism-like features. Among the genes located in the duplicated segment,ACTBgene has been proposed as a candidate gene for the alteration of craniofacial development. Overexpression ofRNF216Lhas been linked to autism. FSCN1 may play a role in neurodevelopmental disease.Conclusion. Characterization of a possible 7p22.1 Duplication Syndrome has yet to be made. Recognition of the clinical spectrum in patients with a smaller duplication of 7p should prove valuable for determining the minimal critical region, helping delineate a better prediction of outcome and genetic counseling

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21

Zhang, Lianzhong, Zhenzhen Wang, Ruifeng Shi, Xuefei Zhu, Jiahui Zhou, Bin Peng, and Xingzhi Xu. "RNF126 Quenches RNF168 Function in the DNA Damage Response." Genomics, Proteomics & Bioinformatics 16, no. 6 (December 2018): 428–38. http://dx.doi.org/10.1016/j.gpb.2018.07.004.

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22

Goyenechea, Estibaliz, Ana B. Crujeiras, Itziar Abete, and J. Alfredo Martínez. "Expression of Two Inflammation-Related Genes (RIPK3 and RNF216) in Mononuclear Cells Is Associated with Weight-Loss Regain in Obese Subjects." Journal of Nutrigenetics and Nutrigenomics 2, no. 2 (2009): 78–84. http://dx.doi.org/10.1159/000210452.

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23

Kumazoe, Motofumi, Yuki Nakamura, Mai Yamashita, Takashi Suzuki, Kanako Takamatsu, Yuhui Huang, Jaehoon Bae, et al. "Green Tea Polyphenol Epigallocatechin-3-gallate Suppresses Toll-like Receptor 4 Expression via Up-regulation of E3 Ubiquitin-protein Ligase RNF216." Journal of Biological Chemistry 292, no. 10 (February 1, 2017): 4077–88. http://dx.doi.org/10.1074/jbc.m116.755959.

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24

Giannini, Ana Lucia, Yifang Gao, and Marie-José Bijlmakers. "T-cell regulator RNF125/TRAC-1 belongs to a novel family of ubiquitin ligases with zinc fingers and a ubiquitin-binding domain." Biochemical Journal 410, no. 1 (January 29, 2008): 101–11. http://dx.doi.org/10.1042/bj20070995.

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The recently identified RNF125 [RING (really interesting new gene) finger protein 125], or TRAC-1 (T-cell RING protein in activation 1), is unique among ubiquitin ligases in being a positive regulator of T-cell activation. In addition, TRAC-1 has been shown to down-modulate HIV replication and to inhibit pathogen-induced cytokine production. However, apart from the presence of an N-terminal C3HC4 (Cys3-His-Cys4) RING domain, the TRAC-1 protein remains uncharacterized. In the present paper, we report novel interactions and modifications for TRAC-1, and elucidate its domain organization. Specifically, we determine that TRAC-1 associates with membranes and is excluded from the nucleus through myristoylation. Our data are further consistent with a crucial role for the C-terminus in TRAC-1 function. In this region, novel domains were recognized through the identification of three closely related proteins: RNF114, RNF138 and RNF166. TRAC-1 and its relatives were found to contain, apart from the RING domain, a C2HC (Cys2-His-Cys)- and two C2H2 (Cys2-His2)-type zinc fingers, as well as a UIM (ubiquitin-interacting motif). The UIM of TRAC-1 binds Lys48-linked polyubiquitin chains and is, together with the RING domain, required for auto-ubiquitination. As a consequence of auto-ubiquitination, the half-life of TRAC-1 is shorter than 30 min. The identification of these novel modifications, interactions, domains and relatives significantly widens the contexts for investigating TRAC-1 activity and regulation.

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25

van Dijk, Jesper R., Yasuo Yamazaki, and Ruth H. Palmer. "Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167/RNF13 identify the PA domain as a determinant for endosomal localization." Biochemical Journal 459, no. 1 (March 14, 2014): 27–36. http://dx.doi.org/10.1042/bj20131067.

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In the present study, we have identified a role for the PA domain of the RNF13/RNF167 ubiquitin ligases, showing that it is both sufficient and required for endosomal localization. Furthermore, although PA domain point-mutations identified from tumours are ligase active, PA mutant proteins are mislocalized within the cell.

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26

Cabana, Valérie C., and Marc P. Lussier. "From Drosophila to Human: Biological Function of E3 Ligase Godzilla and Its Role in Disease." Cells 11, no. 3 (January 23, 2022): 380. http://dx.doi.org/10.3390/cells11030380.

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The ubiquitin–proteasome system is of fundamental importance in all fields of biology due to its impact on proteostasis and in regulating cellular processes. Ubiquitination, a type of protein post-translational modification, involves complex enzymatic machinery, such as E3 ubiquitin ligases. The E3 ligases regulate the covalent attachment of ubiquitin to a target protein and are involved in various cellular mechanisms, including the cell cycle, cell division, endoplasmic reticulum stress, and neurotransmission. Because the E3 ligases regulate so many physiological events, they are also associated with pathologic conditions, such as cancer, neurological disorders, and immune-related diseases. This review focuses specifically on the protease-associated transmembrane-containing the Really Interesting New Gene (RING) subset of E3 ligases. We describe the structure, partners, and physiological functions of the Drosophila Godzilla E3 ligase and its human homologues, RNF13, RNF167, and ZNRF4. Also, we summarize the information that has emerged during the last decade regarding the association of these E3 ligases with pathophysiological conditions, such as cancer, asthma, and rare genetic disorders. We conclude by highlighting the limitations of the current knowledge and pinpointing the unresolved questions relevant to RNF13, RNF167, and ZNRF4 ubiquitin ligases.

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27

Kobayashi, Hatasu, Risako Kabata, Hideyuki Kinoshita, Takaaki Morimoto, Koh Ono, Midori Takeda, Jungmi Choi, et al. "Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice." Pulmonary Circulation 8, no. 3 (May 2, 2018): 204589401877815. http://dx.doi.org/10.1177/2045894018778155.

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Ring finger 213 ( RNF213) is a susceptibility gene for moyamoya disease (MMD), a progressive cerebrovascular disease. Recent studies suggest that RNF213 plays an important role not only in MMD, but also in extracranial vascular diseases, such as pulmonary hypertension (PH). In this study, we undertook genetic screening of RNF213 in patients with PH and performed functional analysis of an RNF213 variant using mouse models. Direct sequencing of the exons in the C-terminal region of RNF213, where MMD-associated mutations are highly clustered, and of the entire coding exons of BMPR2 and CAV1, the causative genes for PH, was performed in 27 Japanese patients with PH. Two MMD-associated rare variants (p.R4810K and p.A4399T) in RNF213 were identified in two patients, three BMPR2 mutations (p.Q92H, p.L198Rfs*4, and p.S930X) were found in three patients, whereas no CAV1 mutations were identified. To test the effect of the RNF213 variants on PH, vascular endothelial cell (EC)-specific Rnf213 mutant transgenic mice were exposed to hypoxia. Overexpression of the EC-specific Rnf213 mutant, but neither Rnf213 ablation nor EC-specific wild-type Rnf213 overexpression, aggravated the hypoxia-induced PH phenotype (high right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels). Under hypoxia, electron microscopy showed unique EC detachment in pulmonary vessels, and western blots demonstrated a significant reduction in caveolin-1 (encoded by CAV1), a key molecule involved in EC functions, in lungs of EC-specific Rnf213 mutant transgenic mice, suggestive of EC dysfunction. RNF213 appears to be a genetic risk factor for PH and could play a role in systemic vasculopathy.

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Mineharu, Yohei, Yuki Oichi, Takahiko Kamata, Yasuzumi Matsui, Takaaki Morimoto, Masahiro Tanji, Hatasu Kobayashi, et al. "MBRS-22. SIGNIFICANCE OF RNF213 IN TUMORGENICITY OF MEDULLOBLASTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii402. http://dx.doi.org/10.1093/neuonc/noaa222.538.

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Abstract RNF213 gene, initially identified as a disease-causing gene for moyamoya cerebrovascular disease, has recently been recognized as a tumor regulator. The gene is known to be associated with WNT signaling, lipid metabolism, angiogenesis and genomic instability. The purpose of this study was to investigate the association of RNF213 in tumorgenicity of medulloblastoma. Incidence of medulloblastoma and histopathological findings were compared among ptch1+/-, ptch1+/- rnf213+/-, and ptch1+/- rnf213-/- mice. Knockout of rnf213 in ptch1+/- transgenic mouse model increased the incidence of spontaneous generation of medulloblastoma from 19.8% (ptch1+/-) to 76.5% (rnf213+/- ptch1+/-) at 9 months (p < 0.001). Heterozygous knockout was equivalent to homozygous knockout. Haploinsufficiency of rnf213 seems to be associated with tumorgenicity in medulloblastoma. Molecular mechanism of medulloblastoma generation needs to be further investigated.

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Bhardwaj, Abhishek, Robert S. Banh, Wei Zhang, Sachdev S. Sidhu, and Benjamin G. Neel. "MMD-associated RNF213 SNPs encode dominant-negative alleles that globally impair ubiquitylation." Life Science Alliance 5, no. 5 (February 8, 2022): e202000807. http://dx.doi.org/10.26508/lsa.202000807.

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Single-nucleotide polymorphisms (SNPs) in RNF213, which encodes a 591-kD protein with AAA+ ATPase and RING E3 domains, are associated with a rare, autosomal dominant cerebrovascular disorder, moyamoya disease (MMD). MMD-associated SNPs primarily localize to the C-terminal region of RNF213, and some affect conserved residues in the RING domain. Although the autosomal dominant inheritance of MMD could most easily explained by RNF213 gain-of-function, the type of ubiquitylation catalyzed by RNF213 and the effects of MMD-associated SNPs on its E3 ligase activity have remained unclear. We found that RNF213 uses the E2-conjugating enzymes UBE2D2 and UBE2L3 to catalyze distinct ubiquitylation events. RNF213-UBED2 catalyzes K6 and, to a lesser extent, K48-dependent poly-ubiquitylation in vitro, whereas RNF213-UBE2L3 catalyzes K6-, K11-, and K48-dependent poly-ubiquitylation events. MMD-associated SNPs encode proteins with decreased E3 activity, and the most frequent MMD allele, RNF213R4810K, is a dominant-negative mutant that decreases ubiquitylation globally. By contrast, MMD-associated RNF213 SNPs do not affect ATPase activity. Our results suggest that decreased RNF213 E3 ligase activity is central to MMD pathogenesis.

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30

Roy, Vincent, Jay P. Ross, Rémy Pépin, Sergio Cortez Ghio, Alyssa Brodeur, Lydia Touzel Deschênes, Gaëtan Le-Bel, et al. "Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function." Stroke 53, no. 4 (April 2022): 1263–75. http://dx.doi.org/10.1161/strokeaha.120.032691.

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Background: Variants in the ring finger protein 213 ( RNF213 ) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease. Methods: To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology. Results: In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines. Conclusions: Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.

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31

Lin, Jing, and Wenli Sheng. "RNF213 Variant Diversity Predisposes Distinct Populations to Dissimilar Cerebrovascular Diseases." BioMed Research International 2018 (December 20, 2018): 1–7. http://dx.doi.org/10.1155/2018/6359174.

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In recent years, the ring finger protein 213 gene (RNF213) has gradually attracted attention, mainly because it has been found that RNF213 c.14429 G>A is associated with moyamoya disease (MMD) in East Asian populations. Recent studies have revealed that RFN213 is not only associated with MMD but is also connected with intracranial major artery stenosis/occlusion (ICASO) and intracranial aneurysm (IA). However, only the relationship between RNF213 c.14429 G>A and ICASO has been confirmed, and whether RNF213 has other mutations related to ICASO remains unclear. RNF213 and IA are currently only confirmed to be correlated in French-Canadian Population and no correlation has been found in the Japanese population. This review summarizes the advances in the associations between RNF213 and different cerebrovascular diseases and highlights that variant diversity of RNF213 may predispose distinct populations to dissimilar cerebrovascular diseases.

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Lu, Youwei, Xi Zhang, Wei Hu, and Qianhong Yang. "The Identification of Candidate Biomarkers and Pathways in Atherosclerosis by Integrated Bioinformatics Analysis." Computational and Mathematical Methods in Medicine 2021 (November 10, 2021): 1–13. http://dx.doi.org/10.1155/2021/6276480.

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Background. Atherosclerosis (AS) is a type of yellow substance containing cholesterol in the intima of large and middle arteries, which is mostly caused by fat metabolism disorders and neurovascular dysfunction. Materials and Methods. The GSE100927 data got analyzed to find out the differentially expressed genes (DEGs) using the limma package in R software. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the DEGs were assessed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) visualized the Protein-Protein Interaction (PPI) network of the aggregated DEGs. GSEA software was used to verify the biological process. Result. We screened 1574 DEGs from 69 groups of atherosclerotic carotid artery and 35 groups of control carotid artery, including 1033 upregulated DEGs and 541 downregulated DEGs. DEGs of AS were chiefly related to immune response, Epstein-Barr virus infection, vascular smooth muscle contraction, and cGMP-PKG signaling pathway. Through PPI networks, we found that the hub genes of AS were PTAFR, VAMP8, RNF19A, VPRBP, RNF217, KLHL42, NEDD4, SH3RF1, UBE2N, PJA2, RNF115, ITCH, SKP1, FBXW4, and UBE2H. GSEA analysis showed that GSE100927 was concentrated in RIPK1-mediated regulated necrosis, FC epsilon receptor fceri signaling, Fceri-mediated NF KB activation, TBC rabgaps, TRAF6-mediated induction of TAK1 complex within TLR4 complex, and RAB regulation of trafficking. Conclusion. Our analysis reveals that immune response, Epstein-Barr virus infection, and so on were major signatures of AS. PTAFR, VAMP8, VPRBP, RNF217, KLHL42, and NEDD4 might facilitate the AS tumorigenesis, which could be new biomarkers for diagnosis and therapy of AS.

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Murai, Yasuo, Eitaro Ishisaka, Atsushi Watanabe, Tetsuro Sekine, Kazutaka Shirokane, Fumihiro Matano, Ryuta Nakae, Tomonori Tamaki, Kenta Koketsu, and Akio Morita. "RNF213 c.14576G>A Is Associated with Intracranial Internal Carotid Artery Saccular Aneurysms." Genes 12, no. 10 (September 23, 2021): 1468. http://dx.doi.org/10.3390/genes12101468.

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A mutation in RNF213 (c.14576G>A), a gene associated with moyamoya disease (>80%), plays a role in terminal internal carotid artery (ICA) stenosis (>15%) (ICS). Studies on RNF213 and cerebral aneurysms (AN), which did not focus on the site of origin or morphology, could not elucidate the relationship between the two. However, a report suggested a relationship between RNF213 and AN in French-Canadians. Here, we investigated the relationship between ICA saccular aneurysm (ICA-AN) and RNF213. We analyzed RNF213 expression in subjects with ICA-AN and atherosclerotic ICS. Cases with a family history of moyamoya disease were excluded. AN smaller than 4 mm were confirmed as AN only by surgical or angiographic findings. RNF213 was detected in 12.2% of patients with ICA-AN and 13.6% of patients with ICS; patients with ICA-AN and ICS had a similar risk of RNF213 mutation expression (odds ratio, 0.884; 95% confidence interval, 0.199–3.91; p = 0.871). The relationship between ICA-AN and RNF213 (c.14576G>A) was not correlated with the location of the ICA and bifurcation, presence of rupture, or multiplicity. When the etiology and location of AN were more restricted, the incidence of RNF213 mutations in ICA-AN was higher than that reported in previous studies. Our results suggest that strict maternal vessel selection and pathological selection of AN morphology may reveal an association between genetic mutations and ICA-AN development. The results of this study may form a basis for further research on systemic vascular diseases, in which the RNF213 (c.14576G>A) mutation has been implicated.

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Ikeuchi, Yasuhito, Jiro Kitayama, Noriyuki Sahara, Takuya Okata, Noriko Miyake, Naomichi Matsumoto, Takanari Kitazono, and Tetsuro Ago. "Filamin A Variant as a Possible Second-Hit Gene Promoting Moyamoya Disease–like Vascular Formation Associated With RNF213 p.R4810K Variant." Neurology Genetics 8, no. 5 (September 9, 2022): e200017. http://dx.doi.org/10.1212/nxg.0000000000200017.

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Background and ObjectiveThe objective of this case report was to identify a second-hit gene that may promote Moyamoya disease (MMD)–like vascular formation in an individual having the RNF213 p.R4810K variant.MethodsWe performed magnetic resonance imaging and genetic analyses of RNF213 and FLNA in a 21-year-old woman, who showed Ehlers-Danlos–like symptoms and developed a first-ever unprovoked seizure, and of her healthy parents.ResultsWe identified bilateral periventricular nodular heterotopia (PNH) as the cause of seizures and MMD-like vascular formation in the patient. The patient had the RNF213 p.R4810K variant. Exome analysis identified c.4868delG in the X-linked FLNA gene encoding filamin A p.G1623V fs*41, which could explain PNH and Ehlers-Danlos–like symptoms. Her mother had the same FLNA variant and had asymptomatic bilateral PNH, whereas her father had the RNF213 variant and had normal cerebrovascular structure.DiscussionThe family study suggested that the FLNA variant promoted MMD-like vascular formation in a patient having the RNF213 variant, while the RNF213 variant amplified the phenotypic changes elicited by the FLNA abnormality. Collectively, we identified a gene abnormality in filamin A, a target of RNF213-mediated proteasomal degradation, that may promote MMD-like vascular formation as a possible second-hit gene in individuals having the RNF213 p.R4810K variant.

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Kadri, Naveen Kumar, Chad Harland, Pierre Faux, Nadine Cambisano, Latifa Karim, Wouter Coppieters, Sébastien Fritz, et al. "Coding and noncoding variants in HFM1, MLH3, MSH4, MSH5, RNF212, and RNF212B affect recombination rate in cattle." Genome Research 26, no. 10 (August 11, 2016): 1323–32. http://dx.doi.org/10.1101/gr.204214.116.

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Kim, Jinkwon, Young Seok Park, Min-Hee Woo, Hui Jeong An, Jung Oh Kim, Han Sung Park, Chang Soo Ryu, Ok Joon Kim, and Nam Keun Kim. "Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms." International Journal of Molecular Sciences 21, no. 6 (March 13, 2020): 1956. http://dx.doi.org/10.3390/ijms21061956.

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Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213, a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213: 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14–4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11–2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.

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Kim, Soomi, Kibeom Park, Jung-Min Oh, and Hongtae Kim. "RNF126 is a positive regulator of TRAF3 ubiquitination." Bioscience, Biotechnology, and Biochemistry 85, no. 12 (October 13, 2021): 2420–28. http://dx.doi.org/10.1093/bbb/zbab177.

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ABSTRACT Ubiquitination and deubiquitination of signaling molecules are critical regulatory mechanisms in various biological contexts such as inflammatory signaling and the DNA damage response. Thus, finely tuned regulation of protein ubiquitination is essential for maintaining cellular homeostasis. Here, we showed that the RING finger protein RNF126 interacts with TRAF3 and promotes its K63-linked polyubiquitination, which is a crucial step in the TRAF3-dependent antiviral response. We found that RNF126 also interacts with OTUB1, a deubiquitinating enzyme that negatively regulates K63-linked ubiquitination of TRAF3. RNF126 promotes ubiquitination of OTUB1, leading to reduced deubiquitinating activity toward TRAF3. Moreover, RNF126 promotes ubiquitination of OTUB1 on cysteine 91, which is reportedly required for its catalytic activity. Taken together, our results suggest that RNF126 positively regulates the antiviral response by directly promoting K63-linked polyubiquitination of TRAF3 and by reducing OTUB1 activity.

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Roy, Vincent, Alyssa Brodeur, Lydia Touzel Deschênes, Nicolas Dupré, and François Gros-Louis. "RNF213 Loss-of-Function Promotes Angiogenesis of Cerebral Microvascular Endothelial Cells in a Cellular State Dependent Manner." Cells 12, no. 1 (December 24, 2022): 78. http://dx.doi.org/10.3390/cells12010078.

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Enhanced and aberrant angiogenesis is one of the main features of Moyamoya disease (MMD) pathogenesis. The ring finger protein 213 (RNF213) and the variant p.R4810K have been linked with higher risks of MMD and intracranial arterial occlusion development in east Asian populations. The role of RNF213 in diverse aspects of the angiogenic process, such as proliferation, migration and capillary-like formation, is well-known but has been difficult to model in vitro. To evaluate the effect of the RNF213 MMD-associated gene on the angiogenic activity, we have generated RNF213 knockout in human cerebral microvascular endothelial cells (hCMEC/D3-RNF213−/−) using the CRISPR-Cas9 system. Matrigel-based assay and a tri-dimensional (3D) vascularized model using the self-assembly approach of tissue engineering were used to assess the formation of capillary-like structures. Quite interestingly, this innovative in vitro model of MMD recapitulated, for the first time, disease-associated pathophysiological features such as significant increase in angiogenesis in confluent endothelial cells devoid of RNF213 expression. These cells, grown to confluence, also showed a pro-angiogenic signature, i.e., increased secretion of soluble pro-angiogenic factors, that could be eventually used as biomarkers. Interestingly, we demonstrated that that these MMD-associated phenotypes are dependent of the cellular state, as only noted in confluent cells and not in proliferative RNF213-deficient cells.

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Jiang, Li, Jiaming Wang, Kai Wang, Hao Wang, Qian Wu, Cong Yang, Yingying Yu, et al. "RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation." Blood 138, no. 8 (April 25, 2021): 689–705. http://dx.doi.org/10.1182/blood.2020008986.

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Abstract Ferroportin (FPN), the body’s sole iron exporter, is essential for maintaining systemic iron homeostasis. In response to either increased iron or inflammation, hepatocyte-secreted hepcidin binds to FPN, inducing its internalization and subsequent degradation. However, the E3 ubiquitin ligase that underlies FPN degradation has not been identified. Here, we report the identification and characterization of a novel mechanism involving the RNF217-mediated degradation of FPN. A combination of 2 different E3 screens revealed that the Rnf217 gene is a target of Tet1, mediating the ubiquitination and subsequent degradation of FPN. Interestingly, loss of Tet1 expression causes an accumulation of FPN and an impaired response to iron overload, manifested by increased iron accumulation in the liver together with decreased iron in the spleen and duodenum. Moreover, we found that the degradation and ubiquitination of FPN could be attenuated by mutating RNF217. Finally, using 2 conditional knockout mouse lines, we found that knocking out Rnf217 in macrophages increases splenic iron export by stabilizing FPN, whereas knocking out Rnf217 in intestinal cells appears to increase iron absorption. These findings suggest that the Tet1-RNF217-FPN axis regulates iron homeostasis, revealing new therapeutic targets for FPN-related diseases.

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da Silva, Zigomar, Werner Giehl Glanzner, Luke Currin, Mariana Priotto de Macedo, Karina Gutierrez, Vanessa Guay, Paulo Bayard Dias Gonçalves, and Vilceu Bordignon. "DNA Damage Induction Alters the Expression of Ubiquitin and SUMO Regulators in Preimplantation Stage Pig Embryos." International Journal of Molecular Sciences 23, no. 17 (August 25, 2022): 9610. http://dx.doi.org/10.3390/ijms23179610.

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DNA damage in early-stage embryos impacts development and is a risk factor for segregation of altered genomes. DNA damage response (DDR) encompasses a sophisticated network of proteins involved in sensing, signaling, and repairing damage. DDR is regulated by reversible post-translational modifications including acetylation, methylation, phosphorylation, ubiquitylation, and SUMOylation. While important regulators of these processes have been characterized in somatic cells, their roles in early-stage embryos remain broadly unknown. The objective of this study was to explore how ubiquitylation and SUMOylation are involved in the regulation of early development in porcine embryos by assessing the mRNA profile of genes encoding ubiquitination (UBs), deubiquitination (DUBs), SUMOylation (SUMOs) or deSUMOylation (deSUMOs) enzymes in oocyte and embryos at different stages of development, and to evaluate if the induction of DNA damage at different stages of embryo development would alter the mRNA abundance of these genes. Pig embryos were produced by in vitro fertilization and DNA damage was induced by ultraviolet (UV) light exposure for 10 s on days 2, 4 or 7 of development. The relative mRNA abundance of most UBs, DUBs, SUMOs, and deSUMOs was higher in oocytes and early-stage embryos than in blastocysts. Transcript levels for UBs (RNF20, RNF40, RNF114, RNF169, CUL5, DCAF2, DECAF13, and DDB1), DUBs (USP16), and SUMOs (CBX4, UBA2 and UBC9), were upregulated in early-stage embryos (D2 and/or D4) compared to oocytes and blastocysts. In response to UV-induced DNA damage, transcript levels of several UBs, DUBs, SUMOs, and deSUMOs decreased in D2 and D4 embryos, but increased in blastocysts. These findings revealed that transcript levels of genes encoding for important UBs, DUBs, SUMOs, and deSUMOs are regulated during early embryo development and are modulated in response to induced DNA damage. This study has also identified candidate genes controlling post-translational modifications that may have relevant roles in the regulation of normal embryo development, repair of damaged DNA, and preservation of genome stability in the pig embryo.

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Hiraide, Takahiro, Hisato Suzuki, Mizuki Momoi, Yoshiki Shinya, Keiichi Fukuda, Kenjiro Kosaki, and Masaharu Kataoka. "RNF213-Associated Vascular Disease: A Concept Unifying Various Vasculopathies." Life 12, no. 4 (April 8, 2022): 555. http://dx.doi.org/10.3390/life12040555.

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The ring finger protein 213 gene (RNF213) encodes a 590 kDa protein that is thought to be involved in angiogenesis. This gene was first recognized as a vasculopathy-susceptibility locus through genome-wide association studies undertaken in a Japanese population, demonstrating that heterozygotes for RNF213 p.Arg4810Lys (c.14429G>A, rs112735431) had a greatly increased risk of moyamoya disease. The association of RNF213 p.Arg4810Lys as a susceptibility variant of moyamoya disease was reproduced in Korean and Chinese individuals and, later, in Caucasians. Variants of the RNF213 gene have been linked to a number of vascular diseases such as moyamoya disease, intracranial major artery stenosis, pulmonary arterial hypertension, and peripheral pulmonary artery stenosis, and have also been associated with co-occurrent diseases and vascular disease in different organs. Based on the findings that we have reported to date, our paper proposes a new concept of “RNF213-associated vascular disease” to unify these conditions with the aim of capturing patients with multiple diseases but with a common genetic background. This concept will be highly desirable for clarifying all of the diseases in the RNF213-associated vascular disease category by means of global epidemiological investigations because of the possibility of such diseases appearing asymptomatically in some patients.

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Wu, Yun, Delin Chen, Yiwen Hu, Shuqing Zhang, Xinhuai Dong, Hao Liang, Minqi Liang та ін. "Ring Finger Protein 215 Negatively Regulates Type I IFN Production via Blocking NF-κB p65 Activation". Journal of Immunology 209, № 10 (15 листопада 2022): 2012–21. http://dx.doi.org/10.4049/jimmunol.2200346.

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Abstract Germline-encoded pattern recognition receptors (PRRs) recognize molecules frequently found in pathogens (pathogen-associated molecular patterns [PAMPs]) during viral infection. This process induces production of IFNs, leading to expression of IFN-stimulated genes to establish a cellular antiviral state against viral infection. However, aberrant activation of the IFN system may cause immunopathological damage and systemic autoimmune diseases such as systemic lupus erythematosus. Stringent control of IFN signaling activation is critical for maintaining homoeostasis of the immune system; yet, the mechanisms responsible for its precise regulation remain to be elucidated. In this study, we identified that ring finger protein 215 (RNF215), a zinc finger protein, was upregulated by viral infection in human macrophages. In addition, we demonstrated that RNF215 inhibited the production of type I IFNs at least in part via interacting with p65, a subunit of NF-κB, and repressed the accumulation of NF-κB in the promoter region of IFNB1. Moreover, we found that the expression of RNF215 negatively correlated with type I IFNs in patients with systemic lupus erythematosus, indicating that RNF215 plays an important role in the pathogenesis of autoimmune diseases. Collectively, our data identified RNF215 as a key negative regulator of type I IFNs and suggested RNF215 as a potential target for intervention in diseases with aberrant IFN production.

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Thư, Lê Nữ Anh, Nguyễn Bá Trung, Dương Thị Hương, Võ Thị Minh Tâm, Dương Thanh Hải, Đinh Văn Dũng, Lê Đình Phùng та Nguyễn Hữu Văn. "ĐA HÌNH GEN NCAPG VÀ RNF212 LIÊN QUAN ĐẾN CÁC TÍNH TRẠNG KINH TẾ Ở BÒ LAI SIND VÀ LAI BRAHMAN NUÔI TẠI MIỀN TRUNG VIỆT NAM". Tạp chí Khoa học và công nghệ nông nghiệp, Trường Đại học Nông Lâm Huế 5, № 1 (28 квітня 2021): 2352–58. http://dx.doi.org/10.46826/huaf-jasat.v5n1y2021.593.

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Sinh sản và sản xuất thịt là những tính trạng kinh tế quan trọng trong sản xuất chăn nuôi. Để cải thiện di truyền những tính trạng này, chỉ thị phân tử đã được ứng dụng rộng rãi ở nhiều nước có hệ thống chăn nuôi phát triển. Những nghiên cứu gần đây cho rằng gen RNF212 và NCAPG liên quan đến khả năng sinh sản và sức sản xuất thịt ở động vật có vú. Trong đó, đột biến thay thế nucleotide đơn C>T trên gen RNF212 được biết làm gia tăng tỷ lệ tái tổ hợp giảm phân ở bò. Hơn nữa, tỷ lệ tái tổ hợp giảm phân tương quan thuận với hiệu quả sinh sản nên đột biến này có thể là chỉ thị quan trọng liên quan đến khả năng sinh sản cao ở bò. Bên cạnh đó, đột biến thay thế nucleotide đơn A>G trên gen NCAPG được biết làm gia tăng khối lượng thịt xẻ ở bò. Do đó, trong nghiên cứu hiện tại, chúng tôi đã tiến hành phân tích đa hình gen RNF212 P259S và NCAPG I442M trên 2 tổ hợp bò lai bằng phương pháp PCR-RFLP. Kết quả phân tích chỉ ra rằng RNF212 P259S và NCAPG I442M là đa hình trong quần thể bò lai Sind và lai Brahman ở Việt Nam. Sự xuất hiện tần suất thấp của alen T (RNF212) và tần suất cao của alen G (NCAPG) có ý nghĩa quan trọng cho công tác chọn và lai tạo giống bò có khả năng sinh sản và năng suất thịt cao. ABSTRACT Reproduction and meat production are considered as the most economically important traits in livestock production. In developed countries, the molecular markers have been commonly used in the animal breeding program to find the favorable alleles in genes associated with economically important traits. The recent studies showed that RNF212 and NCAPG genes are involved in fertility and meat production in mammals, respectively. In which, T allele of RNF212 P259S gene was reported to significantly associate with a higher recombination rate in cow s. Of note, since the meiotic recombination rate correlates positively with the reproductive success of human females, the RNF212 P259S is expected to be a useful marker for increasing the reproductive performance in cattle. In addition, G allele of NCAPG I442M increased the carcass weight of cattle. Therefore, in this study, we conducted the polymorphisms of RNF212 P259S and NCAPG I442M by using PCR-RFLP in 2 crossbred cattle. The results showed that the RNF212 P259S and NCAPG I442M were polymorphic in Red Sindhi and Brahman crossbred cattle. The presence of T allele of RNF212 P259S and G allele of NCAPG I442M are informative for the future breeding of Vietnamese crossbred cattle.

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Phi, Ji Hoon, Jung Won Choi, Moon-Woo Seong, Tackeun Kim, Youn Joo Moon, Joongyub Lee, Eun Jung Koh, et al. "Association between moyamoya syndrome and the RNF213 c.14576G>A variant in patients with neurofibromatosis Type 1." Journal of Neurosurgery: Pediatrics 17, no. 6 (June 2016): 717–22. http://dx.doi.org/10.3171/2015.10.peds15537.

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OBJECTIVE In a minority of patients with neurofibromatosis Type 1 (NF-1), cerebral vasculopathy reminiscent of moyamoya disease develops. This phenomenon is called moyamoya syndrome (MMS), but there are no known risk factors for the prediction of MMS in NF-1 patients. Polymorphism of the RNF213 gene has exhibited strong associations with familial and sporadic moyamoya disease and other cerebral vasculopathies. The aim of this study is to find whether the RNF213 c.14576G>A variant is associated with MMS development in the NF-1 population or not. METHODS The MMS group included 16 NF-1 patients with documented MMS. The control group consisted of 97 NF-1 patients without MMS. Genomic DNA samples were obtained from the saliva or blood of both groups, and the presence of the RNF213 c.14576G>A variant was assessed by Sanger sequencing. RESULTS In the MMS group, 3 patients had the RNF213 c.14576G>A variant (18.7%), whereas no patients with this genetic variation were observed in the control group (0%). There was a meaningful association between the RNF213 c.14576G>A variant and MMS development (p = 0.0024). The crude odds ratio was calculated as 50.57 (95% CI 1.57–1624.41). All 3 patients with MMS and the c.14576G>A variant were diagnosed with MMS at an early age and had bilateral involvement. CONCLUSIONS The RNF213 c.14576G>A variant is more common in NF-1 patients who develop MMS than in NF-1 patients without MMS. This variant might be a susceptibility gene for the NF-1–moyamoya connection.

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Santoro, Claudia, Giuseppe Mirone, Mariateresa Zanobio, Giusy Ranucci, Alessandra D’Amico, Domenico Cicala, Maria Iascone, et al. "Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review." International Journal of Molecular Sciences 23, no. 16 (August 11, 2022): 8952. http://dx.doi.org/10.3390/ijms23168952.

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Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband’s carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118–4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.

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Pollaci, Giuliana, Gemma Gorla, Antonella Potenza, Tatiana Carrozzini, Isabella Canavero, Anna Bersano, and Laura Gatti. "Novel Multifaceted Roles for RNF213 Protein." International Journal of Molecular Sciences 23, no. 9 (April 19, 2022): 4492. http://dx.doi.org/10.3390/ijms23094492.

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Ring Finger Protein 213 (RNF213), also known as Mysterin, is the major susceptibility factor for Moyamoya Arteriopathy (MA), a progressive cerebrovascular disorder that often leads to brain stroke in adults and children. Although several rare RNF213 polymorphisms have been reported, no major susceptibility variant has been identified to date in Caucasian patients, thus frustrating the attempts to identify putative therapeutic targets for MA treatment. For these reasons, the investigation of novel biochemical functions, substrates and unknown partners of RNF213 will help to unravel the pathogenic mechanisms of MA and will facilitate variant interpretations in a diagnostic context in the future. The aim of the present review is to discuss novel perspectives regarding emerging RNF213 roles in light of recent literature updates and dissect their relevance for understanding MA and for the design of future research studies. Since its identification, RNF213 involvement in angiogenesis and vasculogenesis has strengthened, together with its role in inflammatory signals and proliferation pathways. Most recent studies have been increasingly focused on its relevance in antimicrobial activity and lipid metabolism, highlighting new intriguing perspectives. The last area could suggest the main role of RNF213 in the proteasome pathway, thus reinforcing the hypotheses already previously formulated that depict the protein as an important regulator of the stability of client proteins involved in angiogenesis. We believe that the novel evidence reviewed here may contribute to untangling the complex and still obscure pathogenesis of MA that is reflected in the lack of therapies able to slow down or halt disease progression and severity.

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Ishisaka, Eitaro, Atsushi Watanabe, Yasuo Murai, Kazutaka Shirokane, Fumihiro Matano, Atsushi Tsukiyama, Eiichi Baba, et al. "Role of RNF213 polymorphism in defining quasi-moyamoya disease and definitive moyamoya disease." Neurosurgical Focus 51, no. 3 (September 2021): E2. http://dx.doi.org/10.3171/2021.5.focus21182.

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OBJECTIVE Quasi-moyamoya disease (QMMD) is moyamoya disease (MMD) associated with additional underlying diseases. Although the ring finger protein 213 (RNF213) c.14576G>A mutation is highly correlated with MMD in the Asian population, its relationship to QMMD is unclear. Therefore, in this study the authors sought to investigate the RNF213 c.14576G>A mutation in the genetic diagnosis and classification of QMMD. METHODS This case-control study was conducted among four core hospitals. A screening system for the RNF213 c.14576G>A mutation based on high-resolution melting curve analysis was designed. The prevalence of RNF213 c.14576G>A was investigated in 76 patients with MMD and 10 patients with QMMD. RESULTS There were no significant differences in age, sex, family history, and mode of onset between the two groups. Underlying diseases presenting in patients with QMMD were hyperthyroidism (n = 6), neurofibromatosis type 1 (n = 2), Sjögren’s syndrome (n = 1), and meningitis (n =1). The RNF213 c.14576G>A mutation was found in 64 patients (84.2%) with MMD and 8 patients (80%) with QMMD; no significant difference in mutation frequency was observed between cohorts. CONCLUSIONS There are two forms of QMMD, one in which the vascular abnormality is associated with an underlying disease, and the other in which MMD is coincidentally complicated by an unrelated underlying disease. It has been suggested that the presence or absence of the RNF213 c.14576G>A mutation may be useful in distinguishing between these disease types.

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Kim, Hyung Jun, Eun-Hyeok Choi, Jong-Won Chung, Jae-Hwan Kim, Ye Sel Kim, Woo-Keun Seo, Gyeong-Moon Kim, and Oh Young Bang. "Luminal and Wall Changes in Intracranial Arterial Lesions for Predicting Stroke Occurrence." Stroke 51, no. 8 (August 2020): 2495–504. http://dx.doi.org/10.1161/strokeaha.120.030012.

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Background and Purpose: Luminal imaging (degree of stenosis) currently serves as the gold standard to predict stroke recurrence and guide therapeutic strategies in patients with intracranial large artery diseases (ILADs). We comparatively evaluated the importance of vessel wall and luminal changes in predicting stroke occurrence. Methods: Consecutive patients with ILAD in the proximal middle cerebral artery or distal internal carotid artery without proximal sources of embolism from the carotid and heart underwent time-of-flight magnetic resonance angiography, high-resolution magnetic resonance imaging, and the ring finger protein 213 ( RNF213 ) gene variant test. Patients were followed up for >3 months. Results: Of the 675 patients, 241 (35.7%) had atherosclerotic ILAD and 434 (64.3%) showed nonatherosclerotic ILAD (315 [46.7%] moyamoya disease cases and 119 [17.6%] dissection cases). The RNF213 variant was detected in 74.9%, 33.6%, and 3.4% patients with moyamoya disease, atherosclerosis, and dissection, respectively. Three hundred (44.4%) patients had asymptomatic ILAD, whereas 375 (55.6%) patients had symptomatic ILAD. Multivariate analysis showed that vessel enhancement and etiological subtypes, not degree of stenosis, determined by high-resolution magnetic resonance imaging and RNF213 gene variant analysis were independently associated with symptomatic ILAD. The presence of the RNF213 variant was also independently associated with recurrent cerebrovascular events. Conclusions: This study demonstrates the prevalence of nonatherosclerotic ILAD in East Asian patients with ILAD. Unlike luminal changes, wall changes determined by high-resolution magnetic resonance imaging and presence of the RNF213 variant could predict stroke occurrence in patients with ILADs.

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Parrow, Nermi L., and Robert E. Fleming. "RNF217: brokering ferroportin degradation." Blood 138, no. 8 (April 13, 2021): 593–94. http://dx.doi.org/10.1182/blood.2021011496.

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Lake, Cathleen M., and R. Scott Hawley. "RNF212 marks the spot." Nature Genetics 45, no. 3 (February 26, 2013): 228–29. http://dx.doi.org/10.1038/ng.2559.

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