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Wang, Xiaoling, Alan Gerber, Wei-Yi Chen und Robert G. Roeder. „Functions of paralogous RNA polymerase III subunits POLR3G and POLR3GL in mouse development“. Proceedings of the National Academy of Sciences 117, Nr. 27 (23.06.2020): 15702–11. http://dx.doi.org/10.1073/pnas.1922821117.
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Mammalian cells contain two isoforms of RNA polymerase III (Pol III) that differ in only a single subunit, with POLR3G in one form (Pol IIIα) and the related POLR3GL in the other form (Pol IIIβ). Previous research indicates that POLR3G and POLR3GL are differentially expressed, with POLR3G expression being highly enriched in embryonic stem cells (ESCs) and tumor cells relative to the ubiquitously expressed POLR3GL. To date, the functional differences between these two subunits remain largely unexplored, especially in vivo. Here, we show that POLR3G and POLR3GL containing Pol III complexes bind the same target genes and assume the same functions both in vitro and in vivo and, to a significant degree, can compensate for each other in vivo. Notably, an observed defect in the differentiation ability of POLR3G knockout ESCs can be rescued by exogenous expression of POLR3GL. Moreover, whereas POLR3G knockout mice die at a very early embryonic stage, POLR3GL knockout mice complete embryonic development without noticeable defects but die at about 3 wk after birth with signs of both general growth defects and potential cerebellum-related neuronal defects. The different phenotypes of the knockout mice likely reflect differential expression levels of POLR3G and POLR3GL across developmental stages and between tissues and insufficient amounts of total Pol III in vivo.
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Lautré, Wiebke, Elodie Richard, Jean-Paul Feugeas, Hélène Dumay-Odelot und Martin Teichmann. „The POLR3G Subunit of Human RNA Polymerase III Regulates Tumorigenesis and Metastasis in Triple-Negative Breast Cancer“. Cancers 14, Nr. 23 (22.11.2022): 5732. http://dx.doi.org/10.3390/cancers14235732.
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RNA polymerase (Pol) III transcribes short untranslated RNAs that contribute to the regulation of gene expression. Two isoforms of human Pol III have been described that differ by the presence of the POLR3G/RPC32α or POLR3GL/RPC32β subunits. POLR3G was found to be expressed in embryonic stem cells and at least a subset of transformed cells, whereas POLR3GL shows a ubiquitous expression pattern. Here, we demonstrate that POLR3G is specifically overexpressed in clinical samples of triple-negative breast cancer (TNBC) but not in other molecular subtypes of breast cancer. POLR3G KO in the MDA-MB231 TNBC cell line dramatically reduces anchorage-independent growth and invasive capabilities in vitro. In addition, the POLR3G KO impairs tumor growth and metastasis formation of orthotopic xenografts in mice. Moreover, KO of POLR3G induces expression of the pioneer transcription factor FOXA1 and androgen receptor. In contrast, the POLR3G KO neither alters proliferation nor the expression of epithelial–mesenchymal transition marker genes. These data demonstrate that POLR3G expression is required for TNBC tumor growth, invasiveness and dissemination and that its deletion affects triple-negative breast cancer-specific gene expression.
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Malcolm, Jodie R., und Robert J. White. „Alternative isoforms of RNA polymerase III impact the non-coding RNA transcriptome, viability, proliferation and differentiation of prostate cancer cells“. Journal of Translational Genetics and Genomics 6 (2022): 126–33. http://dx.doi.org/10.20517/jtgg.2021.50.
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RNA polymerase III (pol III) synthesizes short noncoding RNA (ncRNA) exclusively and is unique in having alternative paralogues of one of its subunits, POLR3G and POLR3GL. Although most pol III target loci can be transcribed by either isoform, exceptions have been found. For example, depletion of POLR3G curtails the production of BC200 and snaR ncRNAs that are implicated in cancer progression. Furthermore, POLR3G may protect pol III against repression by MAF1, a key physiological regulator. Expression of POLR3G is promoted selectively by MYC, NANOG and OCT4A, master regulators of stem cell pluripotency, resulting in its preferential accumulation in undifferentiated cells. Indeed, differentiation of prostate cancer cells is suppressed by a positive feedback mechanism between POLR3G and NANOG, involving the control of NANOG mRNA degradation by ncRNAs. Specific knockdown of POLR3G inhibits proliferation and induces differentiation of prostate cancer cells, but this response is not seen following comparable depletion of its POLR3GL paralogue. ML-60218 is a cell-permeable small molecule pol III inhibitor that triggers the replacement of POLR3G with POLR3GL. Proliferation and viability of primary prostate cancer cells are suppressed by ML-60218, whereas differentiation is induced, effects that mimic POLR3G depletion. Transient exposure to ML-60218 reduced tumour initiating activity in a xenograft model. Untransformed prostate cells are much less sensitive to these treatments, raising the possibility of therapeutic benefit.
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Renaud, M., V. Praz, E. Vieu, L. Florens, M. P. Washburn, P. l'Hote und N. Hernandez. „Gene duplication and neofunctionalization: POLR3G and POLR3GL“. Genome Research 24, Nr. 1 (09.10.2013): 37–51. http://dx.doi.org/10.1101/gr.161570.113.
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Cheng, Ruiying, Sihang Zhou, Rajendra K C, Simon Lizarazo, Leela Mouli, Anshita Jayanth, Qing Liu und Kevin Van Bortle. „A Combinatorial Regulatory Platform Determines Expression of RNA Polymerase III Subunit RPC7α (POLR3G) in Cancer“. Cancers 15, Nr. 20 (15.10.2023): 4995. http://dx.doi.org/10.3390/cancers15204995.
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RNA polymerase III (Pol III) subunit RPC7α, which is encoded by POLR3G in humans, has been linked to both tumor growth and metastasis. Accordantly, high POLR3G expression is a negative prognostic factor in multiple cancer subtypes. To date, the mechanisms underlying POLR3G upregulation have remained poorly defined. We performed a large-scale genomic survey of mRNA and chromatin signatures to predict drivers of POLR3G expression in cancer. Our survey uncovers positive determinants of POLR3G expression, including a gene-internal super-enhancer bound with multiple transcription factors (TFs) that promote POLR3G expression, as well as negative determinants that include gene-internal DNA methylation, retinoic-acid induced differentiation, and MXD4-mediated disruption of POLR3G expression. We show that novel TFs identified in our survey, including ZNF131 and ZNF207, functionally enhance POLR3G expression, whereas MXD4 likely obstructs MYC-driven expression of POLR3G and other growth-related genes. Integration of chromatin architecture and gene regulatory signatures identifies additional factors, including histone demethylase KDM5B, as likely influencers of POLR3G gene activity. Taken together, our findings support a model in which POLR3G expression is determined with multiple factors and dynamic regulatory programs, expanding our understanding of the circuitry underlying POLR3G upregulation and downstream consequences in cancer.
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Liu, Xianhui, Weiyu Zhang, Huanrui Wang, Chin-Hui Lai, Kexin Xu und Hao Hu. „Increased expression of POLR3G predicts poor prognosis in transitional cell carcinoma“. PeerJ 8 (03.11.2020): e10281. http://dx.doi.org/10.7717/peerj.10281.
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Background Previous studies have shown that RNA Polymerase III Subunit G (POLR3G) has oncogenic effects in cultured cells and mice. However, the role of POLR3G in transitional cell carcinoma (TCC) has not been reported. This study explores the potential of POLR3G as a novel molecular marker for TCC. Methods The RNA sequencing data and clinical information of patients with TCC were downloaded from The Cancer Genome Atlas official website. Transcriptome analysis was performed as implemented in the edgeR package to explore whether POLR3G was up-regulated in TCC tissues compared to normal bladder tissues. The expression of POLR3G in bladder cancer cell line T24 and human uroepithelial cell line SV-HUC-1 were detected via quantitative real time polymerase chain reaction (qRT-PCR). Correlations between POLR3G expression and clinicopathological characteristics were analyzed using Mann-Whitney U test or Kruskal-Wallis H test. Clinicopathological characteristics associated with overall survival were explored using the Kaplan-Meier method and Cox regression analyses. Gene set enrichment analysis (GSEA) was performed to explore the associated gene sets enriched in different POLR3G expression phenotypes and the online tool Tumor IMmune Estimation Resource (TIMER) was used to explore the correlation between POLR3G expression and tumor immune infiltration in TCC. Results Transcriptome analysis showed that POLR3G was significantly up-regulated in TCC tissues compared to normal bladder tissues. Furthermore, qRT-PCR revealed high expression of POLR3G in T24 cells compared to SV-HUC-1 cells. Overall, POLR3G expression was associated with race, tumor status, tumor subtype, T classification, and pathological stage. Kaplan-Meier survival analysis revealed that higher POLR3G expression was associated with lower overall survival. The univariate Cox regression model revealed that age at diagnosis, pathological stage, and POLR3G expression were associated with prognosis of TCC patients. Further multivariate analyses identified these three clinicopathological characteristics as independent prognostic factors for overall survival. GSEA analysis showed that several gene sets associated with tumor development and metastasis, including TGF-β signaling, PI3K-AKT-mTOR signaling, and IL6-JAK-STAT3 signaling, were significantly enriched in POLR3G high expression phenotype. Immune infiltration analysis revealed that the expression of POLR3G was significantly correlated with infiltrating levels of immune cells, including CD8+ T cells, neutrophils, and dendritic cells; and the expression of POLR3G was also significantly correlated with the expression of immune checkpoint molecules, such as PD1, PD-L1, PD-L2, CTLA4, LAG3, HAVCR2, and TIGIT. Conclusions POLR3G was up-regulated in TCC and high POLR3G expression correlated with poor prognosis. POLR3G can potentially be used as a prognostic marker for TCC and might be of great value in predicting the response to immunotherapy.
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Popovich, Sofia G., Lyudmila M. Kuzenkova, Olga B. Kondakova, Alexey I. Firumyants, Tatyana V. Podkletnova und Eugeniya V. Uvakina. „A clinical case of POL3A-associated hypomyelinating leukodystrophy with spinal cord lesion with a debut in early childhood“. L.O. Badalyan Neurological Journal 3, Nr. 3 (30.09.2022): 122–26. http://dx.doi.org/10.46563/2686-8997-2022-3-3-122-126.
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Leukodystrophies are a group of hereditary progressive diseases of the central nervous system characterized by selective lesions in white matter with specific involvement of glial cells. There are hypomyelinating (absence of myelin deposition), demyelinating (loss of previously deposited myelin), dysmyelinating (deposition of structurally or biochemically abnormal myelin), and myelinolytic leukodystrophies (myelin vacuolization). Hypomyelinating leukodystrophies (HL), like most leukodystrophies, debut in childhood or adolescence and are characterized by a progressive course of the disease. HL occurs as a result of impaired synthesis of proteins responsible for the development, structure, and integrity of the myelin sheath, involved in the processes of transcription and translation. In the latter group, the main role is assigned to HL associated with biallelic mutations in the genes of the RNA polymerase III transcription complex, POLR3: POLR3A, POLR3B, POLR1C, and POLR3K. The diagnosis can be confirmed by magnetic resonance imaging of the brain. POLR3A-associated HL is manifested by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. The magnetic resonance features of POLR3-associated HL include diffuse hypomyelination with relative preservation of the dentate nuclei, anterolateral nuclei of the thalamus, globus pallidus, pyramidal tracts at the level of the posterior part of the internal capsules, and the corona radiata. In some cases, thinning of the corpus callosum and atrophy of the cerebellum were also noted. The article presents a clinical case of a patient with POL3A-associated HL with spinal cord injury with the debut in early childhood.
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Kang, Daeun, Chang Ryul Park, Minhyeok Lee, Su Yel Lee, Se Jin Park, Wan Jin Hwang, Gwan Woo Ku et al. „Abstract 817: microRNA-26a-5p is a prognostic factor that regulates cancer stemness“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 817. http://dx.doi.org/10.1158/1538-7445.am2022-817.
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Abstract Background: Cancer stem cells (CSCs) identified in lung cancer exhibit resistance to chemotherapy, radiotherapy, and targeted therapy. Therefore, a technology to control of CSCs is needed to overcome such resistance to cancer therapy. Various evidences about the association between epithelial-mesenchymal transition related transcriptomic alteration and acquisition of CSC phenotype have been proposed recently. In our previous research, down-regulated miR-26a-5p is closely related to mesenchymal-like lung cancer cell lines. These findings suggest that miR-26a-5p might be involved in lung cancer stemness. Methods: RNA polymerase III subunit G (POLR3G) was selected as a candidate target of miR-26a-5p related to cancer stemness. its quantitative relationship was investigated by polymerase chain reaction, western blot after transfection of miR-26a-5p. luciferase assay were done for investigating the direct regulation of miR-26a-5p on POLR3G expression. After transfection of miR-26a-5p, colony formation assay and sphere formation assay were performed to evaluate the effect on cancer stemness. By treating cancer cell by miR-26a-5p and paclitaxel, cell viability was checked by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and Muse cell analyzer. Expression level of each gene and its impact on survival were revealed by the cancer genome atlas pancancer database. Results: miR-26a-5p regulated the expression of POLR3G directly. Overexpression of miR-26a-5p induced down regulation of POLR3G and a marked reduction of colony formation and sphere formation. Co-treatment of miR-26a-5p with paclitaxel decreased cell growth, suggesting that miR-26a-5p might play a role as a chemotherapy sensitizer. In the cancer genome atlas data, down-regulated miR-26a-5p and up-regulated POLR3G were shown compared to adjacent normal tissue. High miR-26a-5p and low POLR3G expression were also related to higher survival rate of patients with lung adenocarcinoma. Conclusions: Overexpression of miR-26a-5p can suppress lung cancer stemness and make cancer cell become sensitive to chemotherapy. This finding provides a novel insight into a potential lung cancer treatment by regulating stemness. Citation Format: Daeun Kang, Chang Ryul Park, Minhyeok Lee, Su Yel Lee, Se Jin Park, Wan Jin Hwang, Gwan Woo Ku, Seong Lan Yu, In Beom Jeong, Sun Jung Kwon, Jaeku Kang, Eung Bae Lee, Ji Woong Son. microRNA-26a-5p is a prognostic factor that regulates cancer stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 817.
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Yang, Hui-Jun, Gyeongmin Park, Il Seong Nam-Goong, Jun-Woo Ahn und Young Cheol Weon. „The First Korean Siblings With Adult-Onset 4H Leukodystrophy Related to Nonsynonymous POLR3B Mutations“. Neurology Genetics 8, Nr. 3 (13.04.2022): e667. http://dx.doi.org/10.1212/nxg.0000000000000667.
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Objectives4H leukodystrophy is a rare autosomal recessive hypomyelinating disorder characterized by several combinations of motor dysfunction, abnormal dentition, and ophthalmic and endocrine abnormalities. To date, only a single Korean case report of pediatric leukodystrophy caused by the POLR1C sequence variation has been published, while there are no reports on the POLR3B, POLR3A, or POLR3K variants.MethodsGenetic tests of Korean sibling pairs with primary amenorrhea due to normosmic isolated hypogonadotropic hypogonadism and cognitive or behavioral symptoms were performed by whole-exome sequencing (WES). The WES results were validated by direct Sanger sequencing.ResultsWe identified biallelic variations in the POLR3B gene of p.Tyr685* and p.Tyr746Cys, which have not been associated with 4H leukodystrophy. Both sequence variants lie in the hybrid-binding domain of the protein RPC2. The protein structure analysis predicted that cysteine substitution of the phylogenetically conserved amino acid tyrosine can cause destabilization.DiscussionThe siblings reported are the first POLR3B-related hypomyelinating leukodystrophy cases in Korea. Our report expands the mutational spectrum of 4H leukodystrophy and suggests that it is mandatory to consider its diagnostic possibility in adult patients presenting with primary amenorrhea and mild cognitive or behavioral symptoms.
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Ahmed, Hakim Si, Ouardia Belarbi, Smail Daoudi, Pierre Labauge, Carra Dallier Clarisse, Schmitt Perrine, Sanchez Pauline, Séverine Drunate und Hélène Cavé. „A new rare homozygous mutation in the POLR3A gene causes ataxo-spasmodic leukodystrophy“. Romanian Journal of Neurology 21, Nr. 2 (30.06.2022): 115–18. http://dx.doi.org/10.37897/rjn.2022.2.4.
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Polymerase III (Pol III) related leukodystrophy is a rare class of leukodystrophy, recently recognized affecting the nervous system and other body systems with typical clinical presentation and imaging results. The diagnosis is made by characteristic combination of clinical signs, brain magnetic resonance imaging results and the presence of pathogenic biallelic mutations in specific genes: POLR3A, POLR3B, POLR3C which encode the RNA polymerase III enzyme subunits. We present the case of a 32-year-old young man who presented with spastic ataxia due to a new rare mutation in the POLR3A gene, splicing variant c.3892-5C > T.
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Pelletier, F., A. Mirchi, FK Cayami, LT Tran, N. Ulrick, C. Polychronakos, A. Vanderver, NI Wolf und G. Bernard. „P.004 Endocrine and growth abnormalities in 4H leukodystrophy patients with a molecular diagnosis“. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 43, S2 (Juni 2016): S22. http://dx.doi.org/10.1017/cjn.2016.110.
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Background: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder characterized by hypomyelination, hypodontia and hypogonadotropic hypogonadism caused by mutations in POLR3A, POLR3B and POLR1C. The endocrine abnormalities have never been systematically studied. Methods: A cross sectional international multicenter study was performed and the following variables were assessed: weight, height, head circumference, pubertal history, hormone levels and neurological and non-neurological features. Data was analyzed to determine whether there was a correlation between the presence of endocrine abnormalities and mutations in a specific gene and/or the presence of specific symptoms such as other non-neurological symptoms. Results: Data was collected on 156 patients. Endocrine data were available for 144 patients. The most common endocrine abnormalities seen in this cohort were short stature (54/90 patients (60%)) and delayed puberty (53/70 patients (76%)). 13 of the 58 patients tested (22%) had abnormal thyroid function. Patients with POLR3A mutations were more likely to have endocrine abnormalities. Conclusions: Our results confirm that the most common endocrine features in 4H leukodystrophy are short stature and pubertal abnormalities. However, the other potential endocrine abnormalities are typically under-investigated in this patient population. A prospective study is required to investigate the extent and severity of the endocrine abnormalities in 4H leukodystrophy.
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Dorboz, Imen, Hélene Dumay-Odelot, Karima Boussaid, Yosra Bouyacoub, Pauline Barreau, Simon Samaan, Haifa Jmel et al. „Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation“. Neurology Genetics 4, Nr. 6 (Dezember 2018): e289. http://dx.doi.org/10.1212/nxg.0000000000000289.
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ObjectiveTo identify the genetic cause of hypomyelinating leukodystrophy in 2 consanguineous families.MethodsHomozygosity mapping combined with whole-exome sequencing of consanguineous families was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients' fibroblasts.ResultsWe identified a biallelic mutation in a gene coding for a Pol III–specific subunit, POLR3K (c.121C>T/p.Arg41Trp), that cosegregates with the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in POLR3A- and POLR3B-related leukodystrophies with a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients' fibroblasts revealed a severe decrease (60%–80%) in the expression of 5S and 7S ribosomal RNAs in comparison with control.ConclusionsThese analyses underlined the key role of ribosomal RNA regulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNA or translation initiation factors.
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Kessler, Alan C., und Richard J. Maraia. „The nuclear and cytoplasmic activities of RNA polymerase III, and an evolving transcriptome for surveillance“. Nucleic Acids Research 49, Nr. 21 (26.11.2021): 12017–34. http://dx.doi.org/10.1093/nar/gkab1145.
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Abstract A 1969 report that described biochemical and activity properties of the three eukaryotic RNA polymerases revealed Pol III as highly distinguishable, even before its transcripts were identified. Now known to be the most complex, Pol III contains several stably-associated subunits referred to as built-in transcription factors (BITFs) that enable highly efficient RNA synthesis by a unique termination-associated recycling process. In vertebrates, subunit RPC7(α/β) can be of two forms, encoded by POLR3G or POLR3GL, with differential activity. Here we review promoter-dependent transcription by Pol III as an evolutionary perspective of eukaryotic tRNA expression. Pol III also provides nonconventional functions reportedly by promoter-independent transcription, one of which is RNA synthesis from DNA 3′-ends during repair. Another is synthesis of 5′ppp-RNA signaling molecules from cytoplasmic viral DNA in a pathway of interferon activation that is dysfunctional in immunocompromised patients with mutations in Pol III subunits. These unconventional functions are also reviewed, including evidence that link them to the BITF subunits. We also review data on a fraction of the human Pol III transcriptome that evolved to include vault RNAs and snaRs with activities related to differentiation, and in innate immune and tumor surveillance. The Pol III of higher eukaryotes does considerably more than housekeeping.
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Kungurtseva, A. L., A. V. Popovich, Y. V. Tikhonovich und A. V. Vitebskaya. „Wiedemann-Rautenstrauch syndrome. The first description of a clinical case in the Russian Federation“. Problems of Endocrinology 70, Nr. 2 (08.10.2023): 86–93. http://dx.doi.org/10.14341/probl13369.
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Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) is an ultra-orphan disease from the group of premature aging syndromes with an autosomal recessive type of inheritance associated with mutations in the POLR3A, POLR3B, and POLR3GL genes encoding RNA polymerase III. The incidence of the disease is currently unknown. We present the first clinical description in Russian Federation of a patient 7 years 6 months old with Wiedemann-Rautenstrauch syndrome (compound heterozygous mutations in POLR3A gene) with progeroid features, adentia, growth retardation (height SDS -3,41, height velocity SDS -2,47), underweight (BMI SDS -6,20), and generalized lipodystrophy. The article presents the observation of the patient for 1.5 years, the world experience of dynamic follow-up of patients with neonatal progeroid syndrome, differential diagnosis, as well as recommendations for the management of patients with this syndrome. Given the lack of specific treatment to date, patients are observed by a multidisciplinary team of physicians.
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Musumeci, Antonino, Francesco Calì, Carmela Scuderi, Mirella Vinci, Girolamo Aurelio Vitello, Sebastiano Antonino Musumeci, Valeria Chiavetta et al. „Identification of a Novel Missense Mutation of POLR3A Gene in a Cohort of Sicilian Patients with Leukodystrophy“. Biomedicines 10, Nr. 9 (14.09.2022): 2276. http://dx.doi.org/10.3390/biomedicines10092276.
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Recessive mutations in the POLR3A gene cause POLR3-HLD (the second-most-common form of childhood-onset hypomyelinating leukodystrophy), a neurodegenerative disorder featuring deficient cerebral myelin formation. To date, more than 140 POLR3A (NM_007055.3) missense mutations are related to the pathogenesis of POLR3-related leukodystrophy and spastic ataxia. Herein, in a cohort of five families from Sicily (Italy), we detected two cases of patients affected by POLR3-related leukodystrophy, one due to a compound heterozygous mutation in the POLR3A gene, including a previously undescribed missense mutation (c.328A > G (p.Lys110Glu)). Our study used an in-house NGS gene panel comprising 41 known leukodystrophy genes. Successively, we used a predictive test supporting the missense mutation as causative of disease, thus this mutation can be considered “Likely Pathogenic” and could be as a new pathogenetic mutation of the POLR3A gene causing a severe form of POLR3-HLD.
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Kungurtseva, A. L., und A. V. Vitebskaya. „Differential Diagnosis of Progeroid Neonatal Syndrome“. Doctor.Ru 22, Nr. 7 (2023): 37–42. http://dx.doi.org/10.31550/1727-2378-2023-22-7-37-42.
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Aim. Аnalysis and synthesis of the literature data on the problem of differential diagnosis of neonatal progeroid syndrome. Key points. One of the rarest representatives of premature aging syndromes is neonatal progeroid syndrome (Wiedemann–Rautenstrauch syndrome). It is an ultra-orphan disease with autosomal recessive type of inheritance, associated with a mutation in the POLR3A, POLR3B, POLR3GL genes and characterized by congenital lipodystrophy and premature aging. The disease manifests from the first days of life: low body length and weight at birth, pronounced phenotypic features (pseudohydrocephaly, progeroid facial features, generalized lipodystrophy, neonatal incisors). Severe bronchopulmonary and skeletal damage is seen over the course of life, and average life expectancy ranges from 7 months to 2 years but can reach 27 years. The differential diagnosis is made with Hutchinson–Gilford syndrome (progeria), which clinical signs manifest at 1.5-2 years of age, and with Marfan-progeroid lipodystrophy, Fontaine syndrome, and Sekkel syndrome. Conclusion. Early diagnostics is necessary for predicting the course of the disease, selection of treatment, and determining of further management. Keywords: neonatal progeroid syndrome, Wiedemann–Rautenstrauch syndrome, premature aging syndromes
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Gauquelin, L., FK Cayami, L. Sztriha, G. Yoon, LT Tran, K. Guerrero, F. Hocke et al. „P.075 Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants“. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 46, s1 (Juni 2019): S34. http://dx.doi.org/10.1017/cjn.2019.175.
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Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
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Dash, Soma, Maureen C. Lamb, Jeffrey J. Lange, Mary C. McKinney, Dai Tsuchiya, Fengli Guo, Xia Zhao et al. „rRNA transcription is integral to phase separation and maintenance of nucleolar structure“. PLOS Genetics 19, Nr. 8 (28.08.2023): e1010854. http://dx.doi.org/10.1371/journal.pgen.1010854.
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Transcription of ribosomal RNA (rRNA) by RNA Polymerase (Pol) I in the nucleolus is necessary for ribosome biogenesis, which is intimately tied to cell growth and proliferation. Perturbation of ribosome biogenesis results in tissue specific disorders termed ribosomopathies in association with alterations in nucleolar structure. However, how rRNA transcription and ribosome biogenesis regulate nucleolar structure during normal development and in the pathogenesis of disease remains poorly understood. Here we show that homozygous null mutations in Pol I subunits required for rRNA transcription and ribosome biogenesis lead to preimplantation lethality. Moreover, we discovered that Polr1a-/-, Polr1b-/-, Polr1c-/- and Polr1d-/- mutants exhibit defects in the structure of their nucleoli, as evidenced by a decrease in number of nucleolar precursor bodies and a concomitant increase in nucleolar volume, which results in a single condensed nucleolus. Pharmacological inhibition of Pol I in preimplantation and midgestation embryos, as well as in hiPSCs, similarly results in a single condensed nucleolus or fragmented nucleoli. We find that when Pol I function and rRNA transcription is inhibited, the viscosity of the granular compartment of the nucleolus increases, which disrupts its phase separation properties, leading to a single condensed nucleolus. However, if a cell progresses through mitosis, the absence of rRNA transcription prevents reassembly of the nucleolus and manifests as fragmented nucleoli. Taken together, our data suggests that Pol I function and rRNA transcription are required for maintaining nucleolar structure and integrity during development and in the pathogenesis of disease.
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Gauquelin, Laurence, Ferdy K. Cayami, László Sztriha, Grace Yoon, Luan T. Tran, Kether Guerrero, François Hocke et al. „Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants“. Neurology Genetics 5, Nr. 6 (30.10.2019): e369. http://dx.doi.org/10.1212/nxg.0000000000000369.
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ObjectiveTo determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants.MethodsA cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed.ResultsFourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified.ConclusionsThis study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
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van Spaendonk, Rosalina, Miriam Nickel, Annette Bley, Kether Guerrero, Luan Tran, Marjo van der Knaap, Geneviève Bernard, Ferdy Cayami, Roberta La Piana und Nicole Wolf. „POLR3A and POLR3B Mutations in Unclassified Hypomyelination“. Neuropediatrics 46, Nr. 03 (08.05.2015): 221–28. http://dx.doi.org/10.1055/s-0035-1550148.
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McQueen, Caitlin, Gideon L. Hughes und Mary E. Pownall. „Skeletal muscle differentiation drives a dramatic downregulation of RNA polymerase III activity and differential expression of Polr3g isoforms“. Developmental Biology 454, Nr. 1 (Oktober 2019): 74–84. http://dx.doi.org/10.1016/j.ydbio.2019.06.001.
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Wong, Raymond Ching-Bong, Sara Pollan, Helen Fong, Abel Ibrahim, Ellen L. Smith, Mirabelle Ho, Andrew L. Laslett und Peter J. Donovan. „A Novel Role for an RNA Polymerase III Subunit POLR3G in Regulating Pluripotency in Human Embryonic Stem Cells“. STEM CELLS 29, Nr. 10 (27.09.2011): 1517–27. http://dx.doi.org/10.1002/stem.714.
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Lund, Riikka J., Nelly Rahkonen, Maia Malonzo, Leni Kauko, Maheswara Reddy Emani, Virpi Kivinen, Elisa Närvä et al. „RNA Polymerase III Subunit POLR3G Regulates Specific Subsets of PolyA + and SmallRNA Transcriptomes and Splicing in Human Pluripotent Stem Cells“. Stem Cell Reports 8, Nr. 5 (Mai 2017): 1442–54. http://dx.doi.org/10.1016/j.stemcr.2017.04.016.
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Sawaguchi, Sui, Rimi Suzuki, Hiroaki Oizumi, Katsuya Ohbuchi, Kazushige Mizoguchi, Masahiro Yamamoto, Yuki Miyamoto und Junji Yamauchi. „Hypomyelinating Leukodystrophy 8 (HLD8)-Associated Mutation of POLR3B Leads to Defective Oligodendroglial Morphological Differentiation Whose Effect Is Reversed by Ibuprofen“. Neurology International 14, Nr. 1 (16.02.2022): 212–44. http://dx.doi.org/10.3390/neurolint14010018.
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POLR3B and POLR3A are the major subunits of RNA polymerase III, which synthesizes non-coding RNAs such as tRNAs and rRNAs. Nucleotide mutations of the RNA polymerase 3 subunit b (polr3b) gene are responsible for hypomyelinating leukodystrophy 8 (HLD8), which is an autosomal recessive oligodendroglial cell disease. Despite the important association between POLR3B mutation and HLD8, it remains unclear how mutated POLR3B proteins cause oligodendroglial cell abnormalities. Herein, we show that a severe HLD8-associated nonsense mutation (Arg550-to-Ter (R550X)) primarily localizes POLR3B proteins as protein aggregates into lysosomes in the FBD-102b cell line as an oligodendroglial precursor cell model. Conversely, wild type POLR3B proteins were not localized in lysosomes. Additionally, the expression of proteins with the R550X mutation in cells decreased lysosome-related signaling through the mechanistic target of rapamycin (mTOR). Cells harboring the mutant constructs did not exhibit oligodendroglial cell differentiated phenotypes, which have widespread membranes that extend from their cell body. However, cells harboring the wild type constructs exhibited differentiated phenotypes. Ibuprofen, which is a non-steroidal anti-inflammatory drug (NSAID), improved the defects in their differentiation phenotypes and signaling through mTOR. These results indicate that the HLD8-associated POLR3B proteins with the R550X mutation are localized in lysosomes, decrease mTOR signaling, and inhibit oligodendroglial cell morphological differentiation, and ibuprofen improves these cellular pathological effects. These findings may reveal some of the molecular and cellular pathological mechanisms underlying HLD8 and their amelioration.
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Cayami, Ferdy, Marianna Bugiani, Petra Pouwels, Geneviève Bernard, Marjo van der Knaap und Nicole Wolf. „4H Leukodystrophy: Lessons from 3T Imaging“. Neuropediatrics 49, Nr. 02 (27.11.2017): 112–17. http://dx.doi.org/10.1055/s-0037-1608780.
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Abstract4H leukodystrophy is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. With its variability in clinical symptoms, application of pattern recognition to identify specific magnetic resonance imaging (MRI) features proved useful for the diagnosis. We collected 3T MR imaging data of 12 patients with mutations in POLR3A (n = 8), POLR3B (n = 3), and POLR1C (n = 1), all obtained at the same scanner. We assessed these images and compared them with previously obtained 1.5T images in 8 patients. Novel MRI findings were myelin islets, closed eye sign, and a cyst-like lesion in the splenium. Myelin islets were variable numbers of small T1 hyperintense and T2 hypointense dots, mostly in the frontal and parietal white matter, and present in all patients. This interpretation was supported with perivascular staining of myelin protein in the hypomyelinated white matter of a deceased 4H patient. All patients had better myelination of the medial lemniscus with a relatively hypointense signal of this structure on axial T2-weighted (T2W) images (“closed eye sign”). Five patients had a small cyst-like lesion in the splenium. In 10 patients with sagittal T2W images, we also found spinal cord hypomyelination. In conclusion, imaging at 3T identified additional features in 4H leukodystrophy, aiding the MRI diagnosis of this entity.
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Marszałek-Kruk, Bożena Anna, Piotr Wójcicki, Krzysztof Dowgierd und Robert Śmigiel. „Treacher Collins Syndrome: Genetics, Clinical Features and Management“. Genes 12, Nr. 9 (09.09.2021): 1392. http://dx.doi.org/10.3390/genes12091392.
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Treacher Collins syndrome (TCS) is associated with abnormal differentiation of the first and second pharyngeal arches, occurring during fetal development. Features of TCS include microtia with conductive hearing loss, slanting palpebral fissures with possibly coloboma of the lateral part of lower eyelids, midface hypoplasia, micrognathia as well as sporadically cleft palate and choanal atresia or stenosis. TCS occurs in the general population at a frequency of 1 in 50,000 live births. Four subtypes of Treacher Collins syndrome exist. TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes. Genetically, the TCOF1 gene contains 27 exons which encodes the Treacle protein. In TCOF1, over 200 pathogenic variants have been identified, of which most are deletions leading to a frame-shift, that result in the formation of a termination codon. In the presented article, we review the genetics and phenotype of TCS as well as the management and surgical procedures utilized for treatment.
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Lamzouri, A., A. EL Rherbi, I. Ratbi, FZ Laarabi, R. Chahboune, SC Elalaoui, H. Hamdaoui, RS Bencheikh und A. Sefiani. „Misdiagnosis of Tracher-Collins Syndrome Initially Attributed to Drug Teratogenicity: A Moroccan Case Report“. Balkan Journal of Medical Genetics 26, Nr. 2 (01.12.2023): 69–72. http://dx.doi.org/10.2478/bjmg-2023-0018.
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Abstract Background Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development characterized by numerous developmental anomalies that are restricted to the head and neck. Most TCS cases are inherited in an autosomal dominant manner. The diagnosis of TCS relies on clinical and radiographic findings. The four genes involved in TCS are TCOF1, POLR1D, POLR1C, and POLR1B. Case presentation In this report, we present the case of a 7-year-old Moroccan boy who exhibited distinctive dysmorphic features, including coloboma and zygomatic bone hypoplasia. Upon genetic analysis, a mutation in the TCOF1 gene was identified, conclusively confirming the presence of Treacher Collins Syndrome. It is worthy that the correct etiological diagnosis was significantly delayed due to the initial misperception that the observed malformation syndrome was a result of drug teratogenicity. Conclusions This case highlights the importance of seeking pharmacovigilance advice if any adverse event occurs following medication use. Furthermore, requesting a genetic consultation to establish a confirmed etiological diagnosis for any malformation syndrome can significantly reduce the protracted social and psychological suffering that patients and their families may endure.
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Wolf, N. I., A. Vanderver, R. M. L. van Spaendonk, R. Schiffmann, B. Brais, M. Bugiani, E. Sistermans et al. „Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations“. Neurology 83, Nr. 21 (22.10.2014): 1898–905. http://dx.doi.org/10.1212/wnl.0000000000001002.
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Yan, Huifang, Haoran Ji, Thomas Kubisiak, Ye Wu, Jiangxi Xiao, Qiang Gu, Yanling Yang et al. „Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing“. Journal of Human Genetics 66, Nr. 8 (18.02.2021): 761–68. http://dx.doi.org/10.1038/s10038-020-00896-5.
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AbstractHypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.
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Takanashi, Jun-ichi, Hitoshi Osaka, Hirotomo Saitsu, Masayuki Sasaki, Harushi Mori, Hidehiro Shibayama, Manabu Tanaka et al. „Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations“. Brain and Development 36, Nr. 3 (März 2014): 259–63. http://dx.doi.org/10.1016/j.braindev.2013.03.006.
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Chen, Qiuxiang, Xiaojing Du, Sunkuan Hu und Qingke Huang. „NF-κB-Related Metabolic Gene Signature Predicts the Prognosis and Immunotherapy Response in Gastric Cancer“. BioMed Research International 2022 (04.01.2022): 1–30. http://dx.doi.org/10.1155/2022/5092505.
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Background. Sufficient evidence indicated the crucial role of NF-κB family played in gastric cancer (GC). The novel discovery that NF-κB could regulate cancer metabolism and immune evasion greatly increased its attraction in cancer research. However, the correlation among NF-κB, metabolism, and cancer immunity in GC still requires further improvement. Methods. TCGA, hTFtarget, and MSigDB databases were employed to identify NF-κB-related metabolic genes (NFMGs). Based on NFMGs, we used consensus clustering to divide GC patients into two subtypes. GSVA was employed to analyze the enriched pathway. ESTIMATE, CIBERSORT, ssGSEA, and MCPcounter algorithms were applied to evaluate immune infiltration in GC. The tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict patients’ response to immunotherapy. We also established a NFMG-related risk score by using the LASSO regression model and assessed its efficacy in TCGA and GSE62254 datasets. Results. We used 27 NFMGs to conduct an unsupervised clustering on GC samples and classified them into two clusters. Cluster 1 was characterized by high active metabolism, tumor mutant burden, and microsatellite instability, while cluster 2 was featured with high immune infiltration. Compared to cluster 2, cluster 1 had a better prognosis and higher response to immunotherapy. In addition, we constructed a 12-NFMG (ADCY3, AHCY, CHDH, GUCY1A2, ITPA, MTHFD2, NRP1, POLA1, POLR1A, POLR3A, POLR3K, and SRM) risk score. Followed analysis indicated that this risk score acted as an effectively prognostic factor in GC. Conclusion. Our data suggested that GC subtypes classified by NFMGs may effectively guide prognosis and immunotherapy. Further study of these NFMGs will deepen our understanding of NF-κB-mediated cancer metabolism and immunity.
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Perrier, Stefanie, Laurence Gauquelin, Catherine Fallet-Bianco, Megan K. Dishop, Mackenzie A. Michell-Robinson, Luan T. Tran, Kether Guerrero et al. „Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy“. Neurology Genetics 6, Nr. 3 (11.05.2020): e425. http://dx.doi.org/10.1212/nxg.0000000000000425.
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ObjectiveTo expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.MethodsWe performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient.ResultsEach patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a POLR3A variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript.ConclusionsWe describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology.
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Hamdan, Zulfiqar, und Diana Alasmar. „Uncertain significance mutation in the POLR3B gene in a Syrian boy with leukodystrophy: a case report“. Annals of Medicine & Surgery 85, Nr. 8 (28.06.2023): 4126–30. http://dx.doi.org/10.1097/ms9.0000000000001033.
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Introduction: 4H leukodystrophy, one of the POLR3-related leukodystrophy, is a rare hereditary brain white matter disease with characteristic clinical presentation and imaging findings. Hypomyelination, hypodontia, and hypogonadotropic hypogonadism is mainly presented in patients with 4H leukodystrophy. Case presentation: A 4-year-old boy presented in the neurologic clinic with delayed psychomotor development and progressive neurologic symptoms that started from the age of 20 months. Physical examination revealed ataxic features and a global development delay. The MRI was significant for hypomyelination. The most common causes of leukodystrophy were rolled out. He was referred to an inherited metabolic disease specialist under suspect of inborn metabolic errors because of laboratory analysis, which showed elevated levels of lactic acid, pyruvate, 4-Hydroxy-Phenylactic acid, 3-Hydroxy propionic acid, and decreased levels of PCO2, HCO3, total CO2, 25-Hydroxyvitamin D. These results were unspecific and mitochondrial disease was highly suspected. However, the genetic study was requested to get a defined diagnosis and treatment; the whole exon sequencing result showed a homozygous variant of uncertain significance mutation; related to an amino acid change from Ile to Thr at position 1002 in the POLR3B gene, which helped us to reveal the final diagnosis, and the genetic counseling were recommended for the next pregnancies. Conclusion: POLR3-related Leukodystrophy is a very rare disease. The early diagnosis should be raised depending on clinical history and MRI findings after other conditions were rolled out, and the confirmed diagnosis depends on the genetic study.
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Saitsu, Hirotomo, Hitoshi Osaka, Masayuki Sasaki, Jun-ichi Takanashi, Keisuke Hamada, Akio Yamashita, Hidehiro Shibayama et al. „Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy“. American Journal of Human Genetics 89, Nr. 5 (November 2011): 644–51. http://dx.doi.org/10.1016/j.ajhg.2011.10.003.
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Michell-Robinson, Mackenzie, Kristin Watt, Vladimir Grouza, Julia Macintosh, Maxime Pinard, Marius Tuznik, Xiaoru Chen et al. „Recapitulation of POLR3-related hypomyelinating leukodystrophy phenotypes in mice using a PDGFRΑ-dependent POLR3B exon-loss genetic model“. Journal of the Neurological Sciences 455 (Dezember 2023): 121280. http://dx.doi.org/10.1016/j.jns.2023.121280.
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Paolacci, Stefano, Yun Li, Emanuele Agolini, Emanuele Bellacchio, Carlos E. Arboleda-Bustos, Dido Carrero, Debora Bertola et al. „Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome“. Journal of Medical Genetics 55, Nr. 12 (15.10.2018): 837–46. http://dx.doi.org/10.1136/jmedgenet-2018-105528.
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BackgroundWiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause.MethodsWe performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants.ResultsBiallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function.ConclusionBiallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.
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Xu, Na, Hanyin Liang, Dongmei Luo, Ziyu Wen, Zicheng Gao, Zherou He, Hong Chen, Xiaoli Liu und Qifa Liu. „Single-Cell RNA Sequencing Uncovers Abnormal Differentiation of Neutrophil and Megakaryocyte Might Mediated Ruxolitinib Resistance for Patinets with PMF“. Blood 142, Supplement 1 (28.11.2023): 6341. http://dx.doi.org/10.1182/blood-2023-184551.
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Background: Primary myelofibrosis (PMF ) is a heterogeneous disorder characterized by bone marrow fibrosis, megakaryocyte hyperplasia, systemic inflammation and extramedullary hematopoiesis. Ruxolitinib (Rux）have shown clinical benefit with reduction of splenomegaly and related symptoms. However, about 50% of patients discontinued ruxolitinib for resistance and/or intolerance，and the mechanism of resistance to ruxolitinib is still unclear. Recently studies found that immune microenvironment and megakaryocyte promote PMF progression, whether the abnormalities of immune microenvironment and megakaryocyte associated with Rux resistance needs to be further elucidated. M ethods: In this study, 8 participants (Newly Diagnosed PMF =3, Resistance to Rux PMF =3, Healthy Donors =2) were included. Peripheral blood was taken and single-cell transcriptome sequencing technology was used. Combined with pseudo-temporal analysis, SCENIC analysis, Single Cell Lineage Inference Using Cell Expression Similarity and Entropy (SLICE), cellular interaction analysis, gene ontology (GO) and Kyoto Gene and Genome Encyclopedia (KEGG) pathway analysis, Gene Set Variation Analysis (GSVA), L-R receptor coexpression analysis and GEPIA online tool for data analysis, Use R language or Python for data processing. Results: In PMF patients, the proportion of neutrophils and monocytes was significantly increased, while the proportion of T cells was significantly decreased in Resistance to Rux group (P<0.05). Further subdivision of neutrophils showed that neutrophils were divided into 6 subgroups. Compared with healthy control group, neutrophils increased in Resistance to Rux group and decreased in Neutrophil_1, among which Neutrophil_6 was only enriched in PMF patients. Neutrophil_6 significantly up-regulated tumor necrosis factor (TNF) superfamily product pathway, IL-1 signaling pathway, Toll-like Receptor 4 (TLR4) signaling pathway, peroxide-producing NADPH oxidase activator activity pathway, MAPK pathway and IL-8 product signaling pathway. Neutrophil_4-6 significantly up-regulates MYB, EZH2, SUZ12, YBX1, POLR3G, E2F7, E2F8 and other transcription factors. L-R up-regulation between Neutrophil_4 and Neutrophil_6 and T cells mediated T cell exhaustion by LGALS9/Tim3 relate to resistance to Rux. We have identified a subset of HSCs in PMF that exhibits a bias towards megakaryocytic/platelet differentiation (HSCs_2) in Rux resistant group. This subset is characterized by the upregulation of specific genes, such as GATA1, PRKAR2B, ITGA2B, PLEK, and KLF1.CellPhoneDB revealed that the regulation of platelets-platelets involves CD40L-CD40 ligand receptors. Notably, the heightened reactivity of platelets may be closely associated with the risk of PMF-related thrombosis. Additionally, we observed an upregulation of the MIF-CD74 cytokine ligand receptor between the immune platelet subsets and HSC subsets in Rux resistant group. Conclusion: In Rux resistant group, Up-regulation of inflammatory and tumor-related signaling pathways promotes the occurrence of PMF inflammation and amplification of malignant clones; Up-regulation of LGALS9 in neutrophil band to receptor TIM3 mediates T cell depletion; the regulation of platelets-platelets in PMF is mediated by CD40L-CD40 ligand receptors; MIF-CD74 might be the relationship between PMF-HSC and PMF-PLT in the context of primary myelofibrosis.
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Ramanathan, Aravind, Michael Weintraub, Natalie Orlovetskie, Raphael Serruya, Dhivakar Mani, Orly Marcu, Polina Stepensky et al. „A mutation in POLR3E impairs antiviral immune response and RNA polymerase III“. Proceedings of the National Academy of Sciences 117, Nr. 36 (25.08.2020): 22113–21. http://dx.doi.org/10.1073/pnas.2009947117.
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RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.
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Churski, Paweł. „Od Redakcji“. Rozwój Regionalny i Polityka Regionalna, Nr. 70 (03.07.2024): 7. http://dx.doi.org/10.14746/rrpr.2024.70s.02.
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W bieżącym numerze specjalnym, zawierającym artykuły z III Polskiej Konferencji Badań Miejskich i Regionalnych POLREG 2023, w miejsce działu Nowości Wydawniczych, zapraszamy Państwa do zapoznania się z komunikatem dotyczącym IV Polskiej Konferencji POLREG 2024, która odbędzie się w dniach 20–22 października 2024 r. w Poznaniu.
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Colona, Vito Luigi, Enrico Bertini, Maria Cristina Digilio, Adele D’Amico, Antonio Novelli, Stefano Pro, Elisa Pisaneschi und Francesco Nicita. „A New Case of Autosomal-Dominant POLR3B-Related Disorder: Widening Genotypic and Phenotypic Spectrum“. Brain Sciences 13, Nr. 11 (08.11.2023): 1567. http://dx.doi.org/10.3390/brainsci13111567.
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POLR3B encodes the RPC2 subunit of RNA polymerase III. Pathogenic variants are associated with biallelic hypomyelinating leukodystrophy belonging to the POLR-related disorders. Recently, the association with dominant demyelinating neuropathy, classified as Charcot–Marie–Tooth syndrome type 1I (CMT1I), has been reported as well. Here we report on an additional patient presenting with developmental delay and generalized epilepsy, followed by the onset of mild pyramidal and cerebellar signs, vertical gaze palsy and subclinical demyelinating polyneuropathy. A new heterozygous de novo missense variant, c.1297C > G, p.Arg433Gly, in POLR3B was disclosed via trio-exome sequencing. In silico analysis confirms the hypothesis on the variant pathogenicity. Our research broadens both the genotypic and phenotypic spectrum of the autosomal-dominant POLR3B-related condition.
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Zanette, Vanessa, Aurelio Reyes, Mark Johnson, Daniel do Valle, Alan J. Robinson, Vaneisse Monteiro, Bruno Augusto Telles et al. „Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations“. Neurology Genetics 6, Nr. 6 (07.10.2020): e521. http://dx.doi.org/10.1212/nxg.0000000000000521.
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ObjectiveTo expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.MethodsWe performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [1H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.ResultsThe patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.ConclusionsMutations in the POLR3A gene cause POLR3A-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.
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Shimada, Kenji, Monika Tsai-Pflugfelder, Niloofar Davoodi Vijeh Motlagh, Neda Delgoshaie, Jeannette Fuchs, Heinz Gut und Susan M. Gasser. „The stabilized Pol31–Pol3 interface counteracts Pol32 ablation with differential effects on repair“. Life Science Alliance 4, Nr. 9 (05.07.2021): e202101138. http://dx.doi.org/10.26508/lsa.202101138.
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DNA polymerase δ, which contains the catalytic subunit, Pol3, Pol31, and Pol32, contributes both to DNA replication and repair. The deletion of pol31 is lethal, and compromising the Pol3–Pol31 interaction domains confers hypersensitivity to cold, hydroxyurea (HU), and methyl methanesulfonate, phenocopying pol32Δ. We have identified alanine-substitutions in pol31 that suppress these deficiencies in pol32Δ cells. We characterize two mutants, pol31-T415A and pol31-W417A, which map to a solvent-exposed loop that mediates Pol31–Pol3 and Pol31–Rev3 interactions. The pol31-T415A substitution compromises binding to the Pol3 CysB domain, whereas Pol31-W417A improves it. Importantly, loss of Pol32, such as pol31-T415A, leads to reduced Pol3 and Pol31 protein levels, which are restored by pol31-W417A. The mutations have differential effects on recovery from acute HU, break-induced replication and trans-lesion synthesis repair pathways. Unlike trans-lesion synthesis and growth on HU, the loss of break-induced replication in pol32Δ cells is not restored by pol31-W417A, highlighting pathway-specific roles for Pol32 in fork-related repair. Intriguingly, CHIP analyses of replication forks on HU showed that pol32Δ and pol31-T415A indirectly destabilize DNA pol α and pol ε at stalled forks.
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Thomas, Aby, und Anna Kalathil Thomas. „POLR3-related Leukodystrophy“. Journal of Clinical Imaging Science 9 (24.10.2019): 45. http://dx.doi.org/10.25259/jcis_116_2019.
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Pol III-related leukodystrophy is a recently recognized category of leukodystrophy with characteristic clinical presentation and imaging findings. These cases are diagnosed by the combination of typical clinical presentation, brain magnetic resonance imaging findings, and the presence of biallelic pathogenic mutations in three specific genes. We present the case of a 6-year-old girl who demonstrated the classic clinical and imaging features of this disorder. This case report aims to raise awareness of this disorder so that it is easily recognized in the appropriate setting.
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Tuyishimire, B., H. Irere, C. Muhizi, A. Ndatinya, O. R. Karangwa, F. Rutarama, C. Nsanzabaganwa und L. Mutesa. „Diagnosis of Treacher-Collins Syndrome: The role of the multidisciplinary team in patient management and family genetic counseling“. Rwanda Medical Journal 79, Nr. 4 (31.12.2022): 9–12. http://dx.doi.org/10.4314/rmj.v79i4.10.
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INTRODUCTION: Although Treacher-Collins syndrome has to be considered a differential diagnosis in congenital craniofacial abnormalities, the clinical diagnosis and research related to it still present a gap, especially in African regions. Thus, this work aims at highlighting this syndrome's clinical features for raising medical awareness. CLINICAL CASE: We reviewed a 1-year-old patient referred to our clinical genetic unit at Rwanda military hospital, Kigali, Rwanda. Physical examinations indicated severe craniofacial abnormalities, including downward-sloping eyes, slight notching of the lower lids, small and underdeveloped eyebrow bones, vision problems, small outer ears, small and underdeveloped cheekbones, and jaw. Within the limits of the techniques used in our laboratory, the cytogenetic analysis revealed a normal karyotype, 46, XY. CONCLUSION: The patient was diagnosed with Treacher-Collins syndrome based on clinical manifestations of craniofacial features. Nevertheless, laboratory tests performed were limited to karyotyping and should not detect any gene defect. Long-term follow-up of the patient and his family was recommended. Further molecular analyses should be performed to identify causing genetic mutation mainly in the TCOF1, POLR1C, or POLR1D genes.
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Chure, Ming Cheng, Ping Cheng Chen, Long Wu, Bing Huei Chen und King Kung Wu. „Influence of Poling Conditions on the Characteristics of PZT Ceramics“. Advanced Materials Research 284-286 (Juli 2011): 1375–80. http://dx.doi.org/10.4028/www.scientific.net/amr.284-286.1375.
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In the poling process of PZT ceramics, the poling temperature is a critical condition. When the poling temperature is too low, no matter how high is the poling field and how long is the poling time, the planar electromechanical coupling factor kpis lower. When the poling temperature is higher enough, the kpcan reach to a saturated value with a lower poling field and short poling time. The variation of dielectric constant with the poling conditions is the same as that of planar electromechanical coupling factor. When poling with a low temperature, the dielectric constant after poling is lower than 1400. When poling with higher temperature, no matter how high is the poling field and how long is the poling time, the dielectric constant after poling is higher than 1500.
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Sawaguchi, Sui, Kenji Tago, Hiroaki Oizumi, Katsuya Ohbuchi, Masahiro Yamamoto, Kazushige Mizoguchi, Yuki Miyamoto und Junji Yamauchi. „Hypomyelinating Leukodystrophy 7 (HLD7)-Associated Mutation of POLR3A Is Related to Defective Oligodendroglial Cell Differentiation, Which Is Ameliorated by Ibuprofen“. Neurology International 14, Nr. 1 (22.12.2021): 11–33. http://dx.doi.org/10.3390/neurolint14010002.
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Hypomyelinating leukodystrophy 7 (HLD7) is an autosomal recessive oligodendroglial cell-related myelin disease, which is associated with some nucleotide mutations of the RNA polymerase 3 subunit a (polr3a) gene. POLR3A is composed of the catalytic core of RNA polymerase III synthesizing non-coding RNAs, such as rRNA and tRNA. Here, we show that an HLD7-associated nonsense mutation of Arg140-to-Ter (R140X) primarily localizes POLR3A proteins as protein aggregates into lysosomes in mouse oligodendroglial FBD−102b cells, whereas the wild type proteins are not localized in lysosomes. Expression of the R140X mutant proteins, but not the wild type proteins, in cells decreased signaling through the mechanistic target of rapamycin (mTOR), controlling signal transduction around lysosomes. While cells harboring the wild type constructs exhibited phenotypes with widespread membranes with myelin marker protein expression following the induction of differentiation, cells harboring the R140X mutant constructs did not exhibit them. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), which is also known as an mTOR signaling activator, ameliorated defects in differentiation with myelin marker protein expression and the related signaling in cells harboring the R140X mutant constructs. Collectively, HLD7-associated POLR3A mutant proteins are localized in lysosomes where they decrease mTOR signaling, inhibiting cell morphological differentiation. Importantly, ibuprofen reverses undifferentiated phenotypes. These findings may reveal some of the pathological mechanisms underlying HLD7 and their amelioration at the molecular and cellular levels.
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Kovalskaia, Valeriia A., Anastasiia L. Kungurtseva, Fatima M. Bostanova, Peter A. Vasiliev, Vyacheslav Y. Tabakov, Mariia D. Orlova, Inna S. Povolotskaya et al. „The Genetic Basis of the First Patient with Wiedemann–Rautenstrauch Syndrome in the Russian Federation“. Genes 15, Nr. 2 (29.01.2024): 180. http://dx.doi.org/10.3390/genes15020180.
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Bi-allelic pathogenic variations within POLR3A have been associated with a spectrum of hereditary disorders. Among these, a less frequently observed condition is Wiedemann–Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome. This syndrome typically manifests neonatally and is characterized by growth retardation, evident generalized lipodystrophy with distinctively localized fat accumulations, sparse scalp hair, and atypical facial features. Our objective was to elucidate the underlying molecular mechanisms of Wiedemann–Rautenstrauch syndrome (WRS). In this study, we present a clinical case of a 7-year-old female patient diagnosed with WRS. Utilizing whole-exome sequencing (WES), we identified a novel missense variant c.3677T>C (p.Leu1226Pro) in the POLR3A gene (NM_007055.4) alongside two cis intronic variants c.1909+22G>A and c.3337-11T>C. Via the analysis of mRNA derived from fibroblasts, we reconfirmed the splicing-affecting nature of the c.3337-11T>C variant. Furthermore, our investigation led to the reclassification of the c.3677T>C (p.Leu1226Pro) variant as a likely pathogenic variant. Therefore, this is the first case demonstrating the molecular genetics of a patient with Wiedemann–Rautenstrauch syndrome from the Russian Federation. A limited number of clinical cases have been documented until this moment; therefore, broadening the linkage between phenotype and molecular changes in the POLR3A gene will significantly contribute to the comprehensive understanding of the molecular basis of POLR3A-related disorders.
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Varela-Gómez, Fernando Fernández, Santiago Vallarta-Compeán, Ingrid Luna-López und Camila Ortiz Tirado-Calderón. „Treacher Collins syndrome: current and emerging treatment options“. International Surgery Journal 11, Nr. 8 (29.07.2024): 1444–49. http://dx.doi.org/10.18203/2349-2902.isj20242150.
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Treacher Collins syndrome is a rare congenital disorder characterized by bilateral craniofacial malformations, including mandibular and zygomatic hypoplasia, cleft palate, and eye anomalies, resulting in significant variability in symptom severity. The syndrome, with an incidence of approximately 1 in 50,000 births, is primarily caused by mutations in the TCOF1 gene and less frequently by mutations in POLR1C and POLR1D genes, disrupting ribosome biogenesis crucial for craniofacial development. Clinical manifestations encompass diverse craniofacial, auditory, and skeletal abnormalities, often leading to airway complications and hearing loss. Management involves a multidisciplinary approach, combining surgical interventions such as mandibular distraction osteogenesis and orthognathic surgeries with advanced imaging techniques for precise planning. Hearing loss is managed with bone conduction aids and cochlear implants, although outcomes may vary due to associated anomalies. Genetic testing aids in diagnosis and family planning decisions, while emerging therapies like genome editing and regenerative medicine show promise for future treatments. Despite challenges in long-term management and relapse rates in surgical corrections, ongoing research aims to enhance therapeutic efficacy and patient outcomes, emphasizing the need for tailored treatment strategies addressing both functional and aesthetic aspects.
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Blagić, Dragan, und Zdravko Grujić. „Criminal Law protection of sexual integrity of a child“. Bezbednost, Beograd 65, Nr. 3 (2023): 83–106. http://dx.doi.org/10.5937/bezbednost2303083b.
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Criminal law protection of a child from sexual violence is very complex in nature and is achieved by prescribing crimes against sexual freedom. In the Serbian criminal legislation, in most criminal offenses, protection is provided for their qualified, i.e. more serious, form. Violation of the sexual integrity of a child in the form of sexual exploitation and abuse is one of the most serious, inhumane, crimes. Systematic study of the phenomenon of endangering the sexual freedom and integrity of child undoubtedly represents a supranational problem and overcomes the mutual social, cultural, religious and other differences of individual states. Criminal law protection is achieved by prescribing certain behaviors as criminal acts, i.e. by stipulating when certain human behaviors can be considered punishable and under what conditions, as well as by prescribing penalties for such acts. It is the most vulnerable category (child) that is placed in a special position according to which sexual freedoms and integrity are most seriously violated and endangered, which inevitably requires initiation of criminal proceedings in order to protect them. On the one hand, in the modern criminal legislation, the legal incrimination is expanding in most criminal acts when it comes to children, because, on the other hand, the number of criminal acts committed to the detriment of children is increasing. In support of this is the fact that the adopted Law on Amendments to the Criminal Code from 2009, in the chapter against sexual freedom, criminalized two new crimes: inducing a child to attend sexual acts (Article 185a) and abuse of computer networks and other technical means of communication for committing crimes against sexual freedom against a minor (Article 185b). The original text of the Criminal Code also contains incriminations of Rape ((Article 178), Sexual Intercourse through Abuse of Position (Article 179), Sexual Intercourse with a Child (Article 180), Showing, Procuring and Possessing Pornographic Material and Minor Person Pornography (Article 185) which provide protection of the child's sexual integrity. The paper analyzes criminal acts that provide basic and additional protection of the child's sexual integrity, but also examines the compliance of new normative solutions with relevant international legal documents in this area, primarily with the Council of Europe Convention on the Protection of Children from Sexual Abuse and Sexual Exploitation.
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Iska, Fachrul Rohimin, Heni Purnamawati und Juang Gema Kartika. „Evaluasi Produktivitas Kacang Tunggak (Vigna unguiculata (L.) Walp) pada Dataran Menengah“. Buletin Agrohorti 6, Nr. 2 (21.05.2018): 171–78. http://dx.doi.org/10.29244/agrob.v6i2.18804.
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Penelitian ini dilakukan untuk mengevaluasi produktivitas kacang tunggak (Vigna unguiculata (L.) Walp) pada dataran menengah. Penelitian dilaksanakan pada dataran menengah di Kampung Cisasah Rawasari, Ciomas, Kabupaten Bogor, Jawa Barat. Penanaman dilakukan pada bulan April 2016 hingga Juli 2016. Penelitian menggunakan Rancangan Kelompok Lengkap Teracak (RKLT) satu faktor. Terdapat lima taraf perlakuan yang digunakan yaitu KT-1, KT-2, KT-6, KT-8 dan KT-9. Perlakuan diulang sebanyak empat kali sehingga terdapat 20 satuan percobaan. Analisis data mengunakan uji F dan apabila hasilnya nyata maka pengujian dilanjutkan dengan uji DMRT (Duncan’s Multiple Range Test) pada taraf 5%. Dilakukan juga uji korelasi beberapa peubah dengan produktivitas. Hasil penelitian menunjukkan bahwa perlakuan varietas berpengaruh sangat nyata terhadap peubah luas daun, jumlah polong per tanaman, bobot biji kering per tanaman, bobot polong kering per tanaman, hasil biji, hasil polong, serta perlakuan varietas berpengaruh nyata terhadap daya tumbuh tanaman dan konduktansi tanaman. Karakter yang berkorelasi positif dan sangat nyata terhadap produktivitas kacang tunggak adalah sudut daun terhadap fotosintesis, sudut daun terhadap konduktansi, fotosintesis terhadap konduktansi, jumlah polong terhadap bobot kering polong, jumlah polong terhadap bobot kering biji, panjang polong terhadap jumlah biji per polong, bobot kering polong terhadap bobot kering biji, jumlah polong terhadap hasil biji, jumlah polong terhadap hasil polong, bobot kering biji terhadap hasil polong.