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Journal articles on the topic 'C16orf35'

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Author: Grafiati
Published: 11 March 2023

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1

Zhou, Guo-Ling, Li Xin, Wei Song, Li-Jun Di, Guang Liu, Xue-Song Wu, De-Pei Liu, and Chih-Chuan Liang. "Active Chromatin Hub of the Mouse α-Globin Locus Forms in a Transcription Factory of Clustered Housekeeping Genes." Molecular and Cellular Biology 26, no. 13 (July 1, 2006): 5096–105. http://dx.doi.org/10.1128/mcb.02454-05.

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ABSTRACT RNA polymerases can be shared by a particular group of genes in a transcription “factory” in nuclei, where transcription may be coordinated in concert with the distribution of coexpressed genes in higher-eukaryote genomes. Moreover, gene expression can be modulated by regulatory elements working over a long distance. Here, we compared the conformation of a 130-kb chromatin region containing the mouse α-globin cluster and their flanking housekeeping genes in 14.5-day-postcoitum fetal liver and brain cells. The analysis of chromatin conformation showed that the active α1 and α2 globin genes and upstream regulatory elements are in close spatial proximity, indicating that looping may function in the transcriptional regulation of the mouse α-globin cluster. In fetal liver cells, the active α1 and α2 genes, but not the inactive ζ gene, colocalize with neighboring housekeeping genes C16orf33, C16orf8, MPG, and C16orf35. This is in sharp contrast with the mouse α-globin genes in nonexpressing cells, which are separated from the congregated housekeeping genes. A comparison of RNA polymerase II (Pol II) occupancies showed that active α1 and α2 gene promoters have a much higher RNA Pol II enrichment in liver than in brain. The RNA Pol II occupancy at the ζ gene promoter, which is specifically repressed during development, is much lower than that at the α1 and α2 promoters. Thus, the mouse α-globin gene cluster may be regulated through moving in or out active globin gene promoters and regulatory elements of a preexisting transcription factory in the nucleus, which is maintained by the flanking clustered housekeeping genes, to activate or inactivate α-globin gene expression.
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2

Kowalczyk, Monika S., Jim R. Hughes, Jacqueline A. Sharpe, Jill M. Brown, Veronica J. Buckle, William G. Wood, and Douglas R. Higgs. "Does Transcription of Remote α-Globin Regulatory Elements Affect Their Function?." Blood 114, no. 22 (November 20, 2009): 4060. http://dx.doi.org/10.1182/blood.v114.22.4060.4060.

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Abstract Abstract 4060 Poster Board III-995 Expression of many tissue and developmental stage specific genes is controlled by remote regulatory elements. The mammalian a-globin gene cluster includes four previously characterised remote regulatory elements (MCS-R1 to R4) upstream of the a-globin genes. Naturally occurring deletions and experiments in transgenic mice, have shown that one or more of these elements are necessary for fully regulated expression of the a-like globin genes. At present it is unclear exactly how these elements interact with the a-globin genes to enhance their expression, although ultimately we know that they physically interact with the promoters forming a chromatin loop. Of interest, three of the MCS-R sequences are located within introns of a widely expressed gene C16orf35, which lies adjacent to the a-globin locus and we now know that such complex, intermingled arrangements are common in the mammalian genome. We have asked two questions: can the MCS-R elements be transcribed while activating the globin genes, and does transcription of the MCS-R elements play any role in their activation? We have analysed nascent transcription of C16orf35 and a-globin, and shown that both genes are simultaneously transcribed in a high proportion of erythroid cells. Thus it appears that the MCS-R elements can interact with the globin genes while being transcribed. We next asked whether transcription of the C16orf35 gene (through the upstream regulatory elements) is necessary for their activation. The promoter region and a putative erythroid-specific promoter of the C16orf35 gene were deleted (singly and in combination) by homologous recombination in mice. Provisional analysis has shown no evidence of a-thalassaemia in these mice, suggesting that activation of the MCS-R elements occurs independently of their transcription. In addition to their importance in globin gene regulation, these findings have general implications for the relationship between structure and function in the mammalian genome and the mechanisms by which long-range elements interact with their cognate promoters. Disclosures: No relevant conflicts of interest to declare.
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3

Lunardi, Andrea, Fulvio Chiacchiera, Elisa D’Este, Marcello Carotti, Marco Dal Ferro, Giulio Di Minin, Giannino Del Sal, and Licio Collavin. "The evolutionary conserved gene C16orf35 encodes a nucleo-cytoplasmic protein that interacts with p73." Biochemical and Biophysical Research Communications 388, no. 2 (October 2009): 428–33. http://dx.doi.org/10.1016/j.bbrc.2009.08.027.

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4

Du, Xinna, Wei Xia, Weiping Fan, Xuan Shen, Hongyan Wu, and Hu Zhang. "Integrated Analysis of C16orf54 as a Potential Prognostic, Diagnostic, and Immune Marker across Pan-Cancer." Disease Markers 2022 (September 9, 2022): 1–25. http://dx.doi.org/10.1155/2022/9365046.

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Chromosome 16 open reading frame 54 (C16orf54) is a protein coding gene, showing a biased expression in the bone marrow, lymph node, and 11 other tissues. Reports on the function of C16orf54 in the onset and development of tumours remain scarce. Clinical information and tumour expression profile data from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx) were utilized to determine the relationship between C16orf54 expression and prognosis, diagnosis, immune microenvironment, heterogeneity, and stemness across pan-cancer. The findings ascertained that C16orf54 was expressed at a low level in most cancers. Furthermore, C16orf54 could distinguish between cancer and normal tissues with high accuracy in most cancers, and the prognostic significance of low C16orf54 mRNA levels differs across cancers. C16orf54 expression was positively linked to the stromal, immune, and ESTIMATE scores. On the other hand, C16orf54 was reported to be negatively correlated with tumour purity in most cancers. Further, C16orf54 expression was positively correlated with immune cell infiltration and the expression of immune regulatory genes, including chemokines, receptors, major histocompatibility complexes, immune inhibitory, and immune stimulatory genes, in most cancers. Additionally, C16orf54 expression was significantly associated with tumour heterogeneity indicators, such as tumour mutation burden (TMB) and microsatellite instability (MSI), and was significantly correlated with DNAss and RNAss tumour stemness indicators. Moreover, Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis, as well as Gene Set Enrichment analysis (GSEA), revealed that C16orf54 expression was closely linked to the signalling pathways of immune cells and factors. The integrated analysis of C16orf54 indicates it as a potential prognostic, diagnostic, and immune marker, which could be adopted as a novel target for adjuvant immunotherapy across pan-cancer.
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5

Nakamura, Toru, Toyomasa Katagiri, Shoki Sato, Toshihiro Kushibiki, Koji Hontani, Takahiro Tsuchikawa, Satoshi Hirano, and Yusuke Nakamura. "Overexpression of C16orf74 is involved in aggressive pancreatic cancers." Oncotarget 8, no. 31 (July 28, 2016): 50460–75. http://dx.doi.org/10.18632/oncotarget.10912.

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6

Afink, Gijs B., Geertruda Veenboer, Janine de Randamie, Remco Keijser, Christof Meischl, Hans Niessen, and Carrie Ris-Stalpers. "Initial Characterization of C16orf89, A Novel Thyroid-Specific Gene." Thyroid 20, no. 7 (July 2010): 811–21. http://dx.doi.org/10.1089/thy.2009.0366.

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7

Li, Tingting, Fei Li, Jia Lin, Yinglan Zhang, Qi Zhang, Yanhe Sun, Xudong Chen, Mingqing Xu, Xu Wang, and Qiang Li. "Deletion of c16orf45 in zebrafish results in a low fertilization rate and increased thigmotaxis." Developmental Psychobiology 62, no. 8 (May 18, 2020): 1003–10. http://dx.doi.org/10.1002/dev.21984.

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8

Bhalla, Kavita, Helen J. Eyre, Scott A. Whitmore, Grant R. Sutherland, and David F. Callen. "C16orf5, a novel proline-rich gene at 16p13.3, is highly expressed in the brain." Journal of Human Genetics 44, no. 6 (October 1999): 383–87. http://dx.doi.org/10.1007/s100380050183.

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9

Arnold, A. W., P. H. Itin, M. Pigors, J. Kohlhase, L. Bruckner-Tuderman, and C. Has. "Poikiloderma with neutropenia: a novel C16orf57 mutation and clinical diagnostic criteria." British Journal of Dermatology 163, no. 4 (July 2, 2010): 866–69. http://dx.doi.org/10.1111/j.1365-2133.2010.09929.x.

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10

Lu, Meng, Qin Xueying, Peng Hexiang, Gao Wenjing, Sara Hägg, Cao Weihua, Li Chunxiao, et al. "Genome-wide associations between alcohol consumption and blood DNA methylation: evidence from twin study." Epigenomics 13, no. 12 (June 2021): 939–51. http://dx.doi.org/10.2217/epi-2021-0039.

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Aim: Alcohol intake alters DNA methylation profiles and methylation might mediate the association between alcohol and disease, but limited number of positive CpG sites repeatedly replicated. Materials & methods: In total, 57 monozygotic (MZ) twin pairs discordant for alcohol drinking from the Chinese National Twin Registry and 158 MZ and dizygotic twin pairs in the Swedish Adoption/Twin Study of Aging were evaluated. DNA methylation was detected using the Infinium HumanMethylation450 BeadChip. Results: Among candidate CpG sites, cg07326074 was significantly correlated with drinking after adjusting for covariates in MZ twins in both datasets but not in the entire sample or dizygotic twins. Conclusion: The hypermethylation of cg07326074, located in the tumor-promoting gene C16orf59, was associated with alcohol consumption.
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11

Kushibiki, Toshihiro, Toru Nakamura, Masumi Tsuda, Takahiro Tsuchikawa, Koji Hontani, Kazuho Inoko, Mizuna Takahashi, et al. "Role of Dimerized C16orf74 in Aggressive Pancreatic Cancer: A Novel Therapeutic Target." Molecular Cancer Therapeutics 19, no. 1 (October 9, 2019): 187–98. http://dx.doi.org/10.1158/1535-7163.mct-19-0491.

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12

Volpi, Ludovica, Gaia Roversi, Elisa Adele Colombo, Nico Leijsten, Daniela Concolino, Andrea Calabria, Maria Antonietta Mencarelli, et al. "Targeted Next-Generation Sequencing Appoints C16orf57 as Clericuzio-Type Poikiloderma with Neutropenia Gene." American Journal of Human Genetics 86, no. 1 (January 2010): 72–76. http://dx.doi.org/10.1016/j.ajhg.2009.11.014.

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13

Volpi, Ludovica, Gaia Roversi, Elisa Adele Colombo, Nico Leijsten, Daniela Concolino, Andrea Calabria, Maria Antonietta Mencarelli, et al. "Targeted Next-Generation Sequencing Appoints C16orf57 as Clericuzio-Type Poikiloderma with Neutropenia Gene." American Journal of Human Genetics 87, no. 3 (September 2010): 445. http://dx.doi.org/10.1016/j.ajhg.2010.08.012.

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14

Sakka, Rania, Bahri Mahjoub, Emna Kerkeni, Amina Werdani, Raoudha Boussoffara, Hassen Ben Cheikh, Ridha M'rad, and Mohamed Taher Sfar. "Poikiloderma with neutropenia in a Tunisian patient with a novel C16orf57 gene mutation." Pediatric Blood & Cancer 65, no. 9 (May 24, 2018): e27262. http://dx.doi.org/10.1002/pbc.27262.

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15

Clericuzio, Carol, Karine Harutyunyan, Weidong Jin, Robert P. Erickson, Alan D. Irvine, W. H. Irwin McLean, Yaran Wen, et al. "Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia." American Journal of Medical Genetics Part A 155, no. 2 (December 22, 2010): 337–42. http://dx.doi.org/10.1002/ajmg.a.33807.

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16

Kilic, Sara S., and Sukru Cekic. "Juvenile Idiopathic Inflammatory Myopathy in a Patient With Dyskeratosis Congenita Due to C16orf57 Mutation." Journal of Pediatric Hematology/Oncology 38, no. 2 (March 2016): e75-e77. http://dx.doi.org/10.1097/mph.0000000000000455.

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17

Carvalho, M. E., F. S. Baldi, M. H. A. Santana, R. V. Ventura, G. A. Oliveira, R. S. Bueno, M. N. Bonin, et al. "Identification of genomic regions related to tenderness in Nellore beef cattle." Advances in Animal Biosciences 8, s1 (October 2017): s42—s44. http://dx.doi.org/10.1017/s2040470017001674.

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The aim of this study was to identify genomic regions that associated with beef tenderness in Nellore cattle. Phenotypes were obtained according to the standard USDA Quality Grade (1999). Data from 909 genotyped Nellore bulls were used in the Genome-Wide Association Study (GWAS) undertaken using a single-step approach including also a pedigree file composed of 6276 animals. The analyses were performed using the Blupf90 software, estimating the effect of genomic windows of 10 consecutive markers. The GWAS results identified 18 genomic regions located on 14 different chromosomes (1, 4, 6, 7, 8, 10, 18, 19, 20, 21, 22, 25, 26 and 29), which explained more than 1% of the total additive genetic variance; several candidate genes were located in these regions including SLC2A9, FRAS1, ANXA3, FAM219A, DNAI, AVEN, SHISA7, UBE2S, CDC42EP5, CNTN3, C16orf96, UBALD1, MGRN1 and SNORA1 With the single-step GWAS, it was possible to identify regions and genes related to meat tenderness in Nellore beef cattle.
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18

Phillips-Krawczak, Christine A., Amika Singla, Petro Starokadomskyy, Zhihui Deng, Douglas G. Osborne, Haiying Li, Christopher J. Dick, et al. "COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A." Molecular Biology of the Cell 26, no. 1 (January 2015): 91–103. http://dx.doi.org/10.1091/mbc.e14-06-1073.

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COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.
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19

Kim, Won Tae, Seok Joong Yun, Cheol Park, Isaac Yi Kim, Sung-Kwon Moon, Tae Gyun Kwon, Yung Hyun Choi, and Wun-Jae Kim. "Identification of C16orf74 as a Marker of Progression in Primary Non-Muscle Invasive Bladder Cancer." PLoS ONE 5, no. 12 (December 21, 2010): e15260. http://dx.doi.org/10.1371/journal.pone.0015260.

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20

Srivastava, Shalini, and Dulal Panda. "A centrosomal protein FOR20 regulates microtubule assembly dynamics and plays a role in cell migration." Biochemical Journal 474, no. 16 (August 10, 2017): 2841–59. http://dx.doi.org/10.1042/bcj20170303.

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Here, we report that a centrosomal protein FOR20 [FOP (FGFR1 (fibroblast growth factor receptor 1) oncogene protein)-like protein of molecular mass of 20 kDa; also named as C16orf63, FLJ31153 or PHSECRG2] can regulate the assembly and stability of microtubules. Both FOR20 IgG antibody and GST (glutathione S-transferase)-tagged FOR20 could precipitate tubulin from the HeLa cell extract, indicating a possible interaction between FOR20 and tubulin. FOR20 was also detected in goat brain tissue extract and it cycled with microtubule-associated proteins. Furthermore, FOR20 bound to purified tubulin and inhibited the assembly of tubulin in vitro. The overexpression of FOR20 depolymerized interphase microtubules and the depletion of FOR20 prevented nocodazole-induced depolymerization of microtubules in HeLa cells. In addition, the depletion of FOR20 suppressed the dynamics of individual microtubules in live HeLa cells. FOR20-depleted MDA-MB-231 cells displayed zigzag motion and migrated at a slower rate than the control cells, indicating that FOR20 plays a role in directed cell migration. The results suggested that the centrosomal protein FOR20 is a new member of the microtubule-associated protein family and that it regulates the assembly and dynamics of microtubules.
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21

Suter, Aude-Annick, Peter Itin, Karl Heinimann, Munaza Ahmed, Tazeen Ashraf, Helen Fryssira, Usha Kini, et al. "Rothmund-Thomson Syndrome: novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene." Molecular Genetics & Genomic Medicine 4, no. 3 (February 24, 2016): 359–66. http://dx.doi.org/10.1002/mgg3.209.

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22

Kojima, Waka, Koji Yamano, Hidetaka Kosako, Kenichiro Imai, Reika Kikuchi, Keiji Tanaka, and Noriyuki Matsuda. "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." Autophagy 17, no. 8 (January 26, 2021): 2011–36. http://dx.doi.org/10.1080/15548627.2021.1874133.

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23

Gong, Junling, Haiying Fan, Jing Deng, and Qiumei Zhang. "LncRNA HAND2‐AS1 represses cervical cancer progression by interaction with transcription factor E2F4 at the promoter of C16orf74." Journal of Cellular and Molecular Medicine 24, no. 11 (April 21, 2020): 6015–27. http://dx.doi.org/10.1111/jcmm.15117.

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24

Fernández, María, Alicia de Coo, Inés Quintela, Eliane García, Márcio Diniz-Freitas, Jacobo Limeres, Pedro Diz, Juan Blanco, Ángel Carracedo, and Raquel Cruz. "Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study." International Journal of Molecular Sciences 22, no. 12 (June 10, 2021): 6274. http://dx.doi.org/10.3390/ijms22126274.

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Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the “Axiom Spanish Biobank” array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10−5, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10−5, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10−5, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10−5, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10−5, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10−2, p = 5.1 × 10−3, p = 1.2 × 10−2, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory response.
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Nazarian, Alireza, Anatoliy I. Yashin, and Alexander M. Kulminski. "Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer’s Disease." Journal of Clinical Medicine 9, no. 5 (May 15, 2020): 1489. http://dx.doi.org/10.3390/jcm9051489.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specific associations with AD, respectively, suggesting a potential role for such epigenetic modifications in the heterogeneous nature of AD. Our analyses provided stronger evidence for possible roles of four genes (i.e., AIM2, C16orf80, DGUOK, and ST14) in AD pathogenesis as they were also transcriptionally associated with AD. The identified associations suggest a list of prioritized genes for follow-up functional studies and advance our understanding of AD pathogenesis.
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26

Dokal, Inderjeet. "Dyskeratosis Congenita." Hematology 2011, no. 1 (December 10, 2011): 480–86. http://dx.doi.org/10.1182/asheducation-2011.1.480.

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Abstract Dyskeratosis congenita (DC) is a multisystem inherited syndrome exhibiting marked clinical and genetic heterogeneity. In its classic form, it is characterized by mucocutaneous abnormalities, BM failure, and a predisposition to cancer. BM failure is the principal cause of premature mortality. Studies over the last 15 years have led to significant advances, with 8 DC genes (DKC1, TERC, TERT, NOP10, NHP2, TIN2, C16orf57, and TCAB1) having been characterized. Seven of these are important in telomere maintenance either because they encode components of the telomerase enzyme complex (DKC1, TERC, TERT, NOP10, NHP2, and TCAB1) or the shelterin complex (TINF2). DC is therefore principally a disease of defective telomere maintenance and patients usually have very short telomeres. The genetic advances have led to the unification of DC with several other disorders, including the severe multisystem disorders Hoyeraal-Hreidarsson and Revesz syndromes, as well as a subset of patients with aplastic anemia, myelodysplasia, leukemia, and idiopathic pulmonary fibrosis. This wide spectrum of diseases ranging from classic DC to aplastic anemia can be regarded as disorders of defective telomere maintenance—“the telomereopathies.” These advances have increased our understanding of normal hematopoiesis and highlighted the important role of telomerase and telomeres in human biology. They are also facilitating the diagnosis (especially when presentation is atypical) and management of DC.
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27

Concolino, D., G. Roversi, G. L. Muzzi, S. Sestito, E. A. Colombo, L. Volpi, L. Larizza, and P. Strisciuglio. "Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with mutations in the C16orf57 gene: Delineation of the phenotype." American Journal of Medical Genetics Part A 152A, no. 10 (August 23, 2010): 2588–94. http://dx.doi.org/10.1002/ajmg.a.33600.

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28

Mroczek, S., J. Krwawicz, J. Kutner, M. Lazniewski, I. Kucinski, K. Ginalski, and A. Dziembowski. "C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3' end modification." Genes & Development 26, no. 17 (August 16, 2012): 1911–25. http://dx.doi.org/10.1101/gad.193169.112.

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29

Danuta, Galetzka, Müller Tobias, Dittrich Marcus, Endres Miriam, Kartal Nergiz, Sinizyn Olesja, Rapp Steffen, et al. "Molecular karyotyping and gene expression analysis in childhood cancer patients." Journal of Molecular Medicine 98, no. 8 (June 23, 2020): 1107–23. http://dx.doi.org/10.1007/s00109-020-01937-4.

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Abstract The genetic etiology of sporadic childhood cancer cases remains unclear. We recruited a cohort of 20 patients who survived a childhood malignancy and then developed a second primary cancer (2N), and 20 carefully matched patients who survived a childhood cancer without developing a second malignancy (1N). Twenty matched cancer-free (0N) and additional 1000 (0N) GHS participants served as controls. Aiming to identify new candidate loci for cancer predisposition, we compared the genome-wide DNA copy number variations (CNV) with the RNA-expression data obtained after in vitro irradiation of primary fibroblasts. In 2N patients, we detected a total of 142 genes affected by CNV. A total of 53 genes of these were not altered in controls. Six genes (POLR3F, SEC23B, ZNF133, C16orf45, RRN3, and NTAN1) that we found to be overexpressed after irradiation were also duplicated in the genome of the 2N patients. For the 1N collective, 185 genes were affected by CNV and 38 of these genes were not altered in controls. Five genes (ZCWPW2, SYNCRIP, DHX30, DHRS4L2, and THSD1) were located in duplicated genomic regions and exhibited altered RNA expression after irradiation. One gene (ABCC6) was partially duplicated in one 1N and one 2N patient. Analysis of methylation levels of THSD1 and GSTT2 genes which were detected in duplicated regions and are frequently aberrantly methylated in cancer showed no changes in patient’s fibroblasts. In summary, we describe rare and radiation-sensitive genes affected by CNV in childhood sporadic cancer cases, which may have an impact on cancer development. Key messages • Rare CNV’s may have an impact on cancer development in sporadic, non-familial, non-syndromic childhood cancer cases. • In our cohort, each patient displayed a unique pattern of cancer-related gene CNVs, and only few cases shared similar CNV. • Genes that are transcriptionally regulated after radiation can be located in CNVs in cancer patients and controls. • THSD1 and GSTT2 methylation is not altered by CNV.
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Lu, Li, Huiyu Li, Xiaomei Chen, Wei Xiong, and Shiang Huang. "The Chromosome Open Reading Frame Genes Targeted By Abnormal Micrornas in Microvesicles from Chronic Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 5509. http://dx.doi.org/10.1182/blood.v124.21.5509.5509.

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Abstract Object: Chronic myeloid leukemia (CML) is a paradigm for neoplasmas that are defined by a unique genetic aberration, the BCR-ABL1 fusion gene. Microvesicles (MVs) are secretory particles released by various cell types including tumor cells. MVs released by CML cells constitute an important part of the microenvironment of leukemia and can modulate the interaction of tumor cells. MicroRNAs (miRNAs) loaded within MVs may also provide an insight in the roles of miRNAs playing in pathological mechanisms of CML. Methods:Blood samples were gathered from patients diagnosed as CML and normal heathy adults. All patients were admitted to Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology during the period from May to September in 2011. Our study was approved by the ethic committee of Wuhan Union Hospital and all subjects signed informed consent. We determined the miRNA expression profiles of CML-derived MVs using Agilent miRNA microarray analysis. Selected miRNAs obtained by microarray profiling were validated using real-time PCR. The putative target genes were predicted by bioinformatic software (TargetScan、miRanda、 PicTar、 MirTart2、PITA). Results:We identified numerous dysregulated miRNAs in MVs derived from CML patients compared with that from the controls by microarray analysis. Of the miRNAs detected, 226 dysregulated miRNAs were present in CML-MVs. With bioinformatic methods, we observed that there were 919 chromosome open reading frame (Corf) genes which were regulated by 169 aberrant MVs miRNAs from CML. Our results indicated that MVs derived from CML were enriched with different groups of altered miRNAs regulating Corf genes. It was interesting that some Corf genes were targeted by one aberrantly expressed MVs miRNAs and that several dysregulated miRNAs targeted one Corf gene. For example, 388 Corf genes were regulated by miR-513a-3p and 186 altered miRNAs targeted C15orf17. These findings suggested that Corf genes were active and complex in non-solid tumors. It was suggested that some members of the Corf genes were closely associated with cancers. For instance, C1orf43, also known as NICE-3 (a novel member of epidermal differentiation complex gene), had been reported to increase tumor cell proliferation and colony formation. In addition, deletion of C8orf4 was correlated with the risk of hematological neoplasmas. Furthermore, C16orf74, negatively associated with development of malignancies, was targeted by over-expressed miR-1299. Given that miRNAs could inhibit the expression of target genes, antineoplastic functions of C16orf74 might be suppressed. Similarly, C11orf30 that was a key oncogene was targeted by down-expressed miR-93, which facilitated C11orf30 to produce tumor-promoting roles. Interestingly, we observed that several Corf genes acting as oncogenes were regulated by over-expressed miRNAs. For instance, C6orf211 and C19orf10 were positively correlated with tumor progression and both of them were regulated by up-regulated miRNAs including miR-1246 and miR-1305. This indicated that Corf genes in diverse tumor microenvironments were likely to exert different influence on carcinogenesis. Conclusion: Briefly, we demonstrated for the first time that CML-derived MVs were enriched with dysregulated miRNAs targeting Corf genes, indicating that miRNAs regulating Corf genes were active in CML-MVs. Furthermore, Corf genes regulated by distinct sets of altered miRNAs might produce similar or alien effects on tumor progression. Disclosures No relevant conflicts of interest to declare.
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Colombo, Elisa A., J. Fernando Bazan, Gloria Negri, Cristina Gervasini, Nursel H. Elcioglu, Deniz Yucelten, Ilknur Altunay, et al. "Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations." Orphanet Journal of Rare Diseases 7, no. 1 (2012): 7. http://dx.doi.org/10.1186/1750-1172-7-7.

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Walne, Amanda J., Tom Vulliamy, Richard Beswick, Michael Kirwan, and Inderjeet Dokal. "Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund–Thomson syndrome." Human Molecular Genetics 19, no. 22 (September 3, 2010): 4453–61. http://dx.doi.org/10.1093/hmg/ddq371.

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Dereure, O. "Des mutations du gène C16orf57 sont impliquées dans le syndrome poïkilodermie – neutropénie et dans une variété particulière de dyskératose congénitale à télomères normaux." Annales de Dermatologie et de Vénéréologie 138, no. 4 (April 2011): 362–63. http://dx.doi.org/10.1016/j.annder.2011.01.026.

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34

Young, Corey D., Eric B. Dammer, Ti'ara L. Griffen, Sha'kayla K. Nunez, Courtney Dill, Kaylin M. Carey, and James W. Lillard. "Abstract 2950: Coexpression networks of miRNAs and gene transcripts coinciding with lung adenocarcinoma progression and survival." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2950. http://dx.doi.org/10.1158/1538-7445.am2022-2950.

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Abstract Lung & bronchus cancer is the second most diagnosed cancer, causing the most cancer-related deaths in the United States. A lung and bronchus subtype, NSCLC (non-small cell lung cancer), accounts for over 75% of new lung cancer diagnoses of which lung adenocarcinoma (LUAD) is the most common. Here, we studied the role of microRNAs and the transcriptome expression profile in LUAD prognosis, progression, and overall patient survival. We analyzed RNA-sequence data from a cohort of LUAD patients from The Cancer Genome Atlas (TCGA). The correlations of microRNA gene expression to transcription networks identified by weighted gene co-expression network analysis (WGCNA) were further explored in an upstream regulator/signaling pathway analysis, gene ontology (GO) process enrichment, and differential expression analysis. Mature microRNA abundance was also integrated with the mRNA network via correlation analysis. Our analysis revealed 18 clusters (modules) of highly correlated gene transcripts. The turquoise and red modules were of particular interest, as they were correlated negatively with overall survival, positively with stage 1 status, and negatively to later pathologic stages (3-4). Additionally, high select miRNA correlation to the red module transcripts (e.g., C16Orf89, ADGRF5, CFAP221, and SELENBP1; all with module eigengene correlation rho ≥ 0.75), and to the turquoise module (e.g., DDX39B and LENG8; each with rho ≥ 0.85) suggests these are miRNA-mRNA coregulatory networks of which both the gene products and potentially upstream miRNAs may serve as promising mechanistic targets and prognostic markers for LUAD, meriting further study. Citation Format: Corey D. Young, Eric B. Dammer, Ti'ara L. Griffen, Sha'kayla K. Nunez, Courtney Dill, Kaylin M. Carey, James W. Lillard. Coexpression networks of miRNAs and gene transcripts coinciding with lung adenocarcinoma progression and survival [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 2950.
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Jeong, Ho-Chang, Siddharth Shukla, Roy Parker, and Luis Batista. "USB1 Is a miRNA Deadenylase That Regulates Hematopoietic Development." Blood 138, Supplement 1 (November 5, 2021): 2191. http://dx.doi.org/10.1182/blood-2021-146115.

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Abstract Poikiloderma with neutropenia (PN)is an autosomal-recessive bone marrow failure (BMF) syndrome in which patients harbor homozygous or compound heterozygous mutations in the human gene C16orf57, which encodes the evolutionarily conserved RNA 3' to 5' exonuclease U6 biogenesis 1 (USB1). USB1 is required for the proper maturation of U6 and U6atac snRNAs, core components of the spliceosome, and consequently, splicing defects have been observed in yeast and zebrafish models with USB1 deficiency. However, lymphoblastoid cells from PN patients do not exhibit reduced U6 snRNA levels and have normal pre-mRNA splicing, establishing PN as a singular BMF syndrome, where the underlying genetic cause has been identified but the molecular mechanisms leading to tissue failure remain obscure. To investigate the role of USB1 in a physiological context, we utilized CRISPR/Cas9 to create human embryonic stem cells (hESCs) containing a frequently occurring c.531_del_A loss-of-function mutation in the USB1 gene (USB1_c.531_del_A hESCs). USB1_c.531_del_A hESCs have normal karyotype, normal growth rate, and retain pluripotency, indicating that clinically-relevant mutations in USB1 are not deleterious in undifferentiated hESCs. To elucidate the role of USB1 during hematopoiesis, we performed serum-free hematopoietic differentiations to derive hematopoietic progenitor cells from WT and USB1_c.531_del_A hESCs. The formation of definitive hematopoietic progenitors (CD45+) was decreased in USB1 mutant cells compared to WT cells, and definitive colony potential analysis showed compromised colony formation in USB1 mutants. These observations indicate that loss-of-function mutations in USB1 negatively influence hematopoiesis. Additionally, as PN is associated with severe non-cyclic neutropenia, we analyzed the potential of neutrophil formation in WT and USB1 mutant cells. USB1 mutants have reduced formation of CD15+/CD66b+ lineages, indicating abnormal neutrophil development. Conditional expression of WT USB1 in USB1_c.531_del_A mutant cells rescued these phenotypes, leading to normal hematopoietic development. Interestingly, USB1 mutants showed no reduction in the overall levels of U6 and U6atac snRNAs, similar to what was observed in patient cells. To identify other possible targets of USB1, we sequenced the transcriptome and miRome of WT and USB1 mutant cells in different stages of hematopoietic development. Through these analyses, we demonstrate that hematopoietic failure in USB1 mutants is caused by dysregulated miRNA levels during blood development, due to a failure to remove destabilizing 3' end oligo(A) tails added by PAPD5/7. Moreover, we demonstrate that modulation of oligoadenylation through genetic or chemical inhibition of PAPD5/7 rescues the defective hematopoiesis observed in USB1 mutants. This work indicates USB1 acts as a miRNA deadenylase and suggests PAPD5/7 inhibition as a potential therapy for PN. Disclosures Parker: Faze Therapeutics: Other: Co-founder.
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Baratti, Mariana O., Yuri B. Moreira, Fabiola Traina, Luciene Borges, Fernando F. Costa, Sergio Verjovski-Almeida, and Sara T. O. Saad. "Identification of Intronic RNA Expression in CD34+ Cells of Patients with Myelodysplatic Syndrome by RNA Microarray Analysis." Blood 110, no. 11 (November 16, 2007): 2423. http://dx.doi.org/10.1182/blood.v110.11.2423.2423.

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Abstract Myelodysplatic syndromes (MDS) are a group of clonal hematological disorders characterized by ineffective hematopoiesis with morphological evidence of marrow cell dysplasia resulting in peripheral blood cytopenia. Microarray technology has permitted a refined high-throughput mapping of the transcriptional activity in the human genome. RNAs transcribed from intronic regions of genes are involved in a number of processes related to post-transcriptional control of gene expression, and in the regulation of exon-skipping and intron retention. The characterization of intronic transcripts in progenitor cells of MDS patients could be an important strategic to understand the gene expression regulation in this disease. We conducted a pilot study in CD34+ cells of 4 MDS-RARS patients and 4 healthy individuals. Gene expression analysis was performed using a 44k intron-exon oligoarray custom-designed by Verjorvski-Almeida et al. and printed by Agilent Technologies. This oligoarray included protein-coding genes, sense and antisense strands of totally intronic noncoding (TIN) and partially intronic nonconding (PIN) RNAs. CD34+ cells were isolated from bone marrow samples using MACS magnetic columns. The quality of total extracted RNA was confirmed with the Agilent Bioanalyzer 2100. We amplified 300ng of each total RNA using the Agilent Low RNA Input Fluorescent Linear Amplification Kit PLUS, two-Color and samples were hybridized using the Gene Expression Hybridization Kit (Agilent) and then scanned on a GenePIX 4000B Scanner (Molecular Devices). The extraction analysis was performed using Agilent Feature Extration Software 9.5. Considering only the fluorescent spots in samples, the data were normalized by quantil using Spotfire DecisionSite®. To identify genes differentially expressed between MDS-RARS and healthy samples, we applied the SAM (Significance Analysis of microarray) approach using as parameters: two-class unpaired response, t-statistic, 1,000 permutations, fold > 2 and FDR = 0%. We identified 139 genes differentially expressed (67 up-regulated and 72 down-regulated), of which 33 were TIN and PIN transcripts (21 up-regulated and 12 down-regulated). These transcripts were grouped according to the main role: gene transcription (ZNF76, CC2D1A, ASXL1, TOP2B, NR4A3 and NR4A2); immune response (CTSH, CTSS, IFI30, NPY, SERPINA1 and PAG1); growth factor and receptor (RP5-1022P6.2, PRG4 and FGFR1OP2); adhesion (PPP1R15A and FN1); cell differentiation (B3GNT5, RALGPS1, C16orf67 and C5orf13); cell cycle and apoptosis (CYFIP2, PPP1R15A, DDX3X and NASP) and cellular trafficking (WIPI1, ICA1 and SLC11A2). These results demonstrated that 22% of all the genes differentially expressed correspond to TIN and PIN transcripts in CD34+ cells of MDS-RARS patients, suggesting that intronic transcripts can play an important role during the development of myelodysplastic syndrome.
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Westin, Erik, Larisa Pereboeva, Divya Devadasan, Tim M. Townes, and Frederick D. Goldman. "Suppression of Antioxidant Responses in Dyskeratosis Congenita Cells." Blood 126, no. 23 (December 3, 2015): 2412. http://dx.doi.org/10.1182/blood.v126.23.2412.2412.

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Abstract Dyskeratosis Congenita (DC) is a bone marrow failure disorder characterized by a triad of leukoplakia, skin dyspigmentation and nail dystrophy. Pathologies found in these patients arise due to mutations found within a number of genes (DKC1, TERT, TERC, TINF2, TCAB1, CTC1, NOP10, C16orf57, NHP2 and PARN) that limit telomere maintenance/elongation, resulting in severely shortened telomeres. Previous studies in our lab have demonstrated impaired proliferation, limited lifespan and aberrant DNA damage response pathways in DC cells. These studies have also uncovered a significant reactive oxygen species (ROS) increase within every cell type investigated thus far. This ROS increase correlates with telomere dysfunction and the subsequent activation of the p53 DNA damage response pathway, which can be rescued by exogenous TERT or p53-shRNA expression. We have acquired skin punch biopsies from two patients with DC carrying either a TERT or DKC1 mutation. Here, we have investigated a potential candidate pathway largely characterized as a key antioxidant regulator in hematopoietic cells, NRF2 (NFE2L2). NRF2 is a redox-sensitive basic leucine zipper transcription factor that, together with its heterologous partners (small MAF proteins, cJun, ATF, etc), binds to antioxidant response elements (AREs) within gene promoters in a pro-oxidant environment. We compared the RNA expression via QRTPCR of NRF2 in control and DC skin fibroblasts and found a significant reduction in DC cells (TERT mutation: 1.5 fold; DKC1 mutation: 2.6 fold). Protein levels of NRF2 were also decreased in DC fibroblasts compared to controls. TXN is a gene whose expression is increased by NRF2 in a pro-oxidant environment. TXN expression was also significantly reduced (TERT mutation: 2.1 fold; DKC1 mutation: 2.2 fold). To test whether NRF2 suppression in DC cells is due to telomere dysfunction, we exogenously expressed TERT via retrovirus in DC and control fibroblasts. TERT expression led to dramatic increases in NRF2 (TERT mutation: 3.4 fold, DKC1 mutation: 3.7 fold) and TXN (TERT mutation: 3.7 fold, DKC1 mutation: 1.6 fold). In contrast, TERT expression in control cells increased NRF2 only 1.3 fold while TXN decreased 1.4 fold. Finally, we wanted to compare the expression of NRF2/TXN in low and elevated oxidative environments (4% vs 21% O2). Control cells increased the TXN expression in 21% O2 (NRF2: no change, TXN: 2.8 fold) while DC cells suppressed NRF2 (TERT mutation: no change, DKC1 mutation: 3 fold decrease) and TXN expression (TERT mutation: 1.4 fold decrease, DKC mutation: 2.3 fold decrease). Functional studies have found DC cells grown in low oxygen increase their proliferative capacity perhaps due to, in part, the NRF2 pathway. Together, these data support a hypothesis whereby shortened/dysfunctional telomeres suppress NRF2 activity and an antioxidant response to a pro-oxidant environment. Based upon previous research, this pathway is likely dependent on the activation of p53 as an intermediary between dysfunctional telomere signaling and the subsequent suppression of NRF2 activity. An abrogated antioxidant response in shortened telomere cells may promote entry into senescence and pathologies related to aging. Systemic pharmacological intervention that reduces ROS could reverse this process and form the basis to alleviate DC and related symptomology associated with this multi-organ disorder. Disclosures No relevant conflicts of interest to declare.
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Jansen, Iris E., Sven J. van der Lee, Duber Gomez-Fonseca, Itziar de Rojas, Maria Carolina Dalmasso, Benjamin Grenier-Boley, Anna Zettergren, et al. "Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers." Acta Neuropathologica, September 6, 2022. http://dx.doi.org/10.1007/s00401-022-02454-z.

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AbstractAmyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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39

Benslimane, Yahya, María Sánchez‐Osuna, Jasmin Coulombe‐Huntington, Thierry Bertomeu, Danielle Henry, Caroline Huard, Éric Bonneil, Pierre Thibault, Mike Tyers, and Lea Harrington. "A novel p53 regulator, C16ORF72/TAPR1, buffers against telomerase inhibition." Aging Cell 20, no. 4 (March 4, 2021). http://dx.doi.org/10.1111/acel.13331.

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40

Amici, David R., Harun Cingoz, Milad J. Alasady, Sammy Alhayek, Claire M. Phoumyvong, Nidhi Sahni, S. Stephen Yi, and Marc L. Mendillo. "The HAPSTR2 retrogene buffers stress signaling and resilience in mammals." Nature Communications 14, no. 1 (January 11, 2023). http://dx.doi.org/10.1038/s41467-022-35697-1.

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AbstractWe recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1’s canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.
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Amici, David R., Daniel J. Ansel, Kyle A. Metz, Roger S. Smith, Claire M. Phoumyvong, Sitaram Gayatri, Tomasz Chamera, et al. "C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways." Proceedings of the National Academy of Sciences 119, no. 27 (July 2022). http://dx.doi.org/10.1073/pnas.2111262119.

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All cells contain specialized signaling pathways that enable adaptation to specific molecular stressors. Yet, whether these pathways are centrally regulated in complex physiological stress states remains unclear. Using genome-scale fitness screening data, we quantified the stress phenotype of 739 cancer cell lines, each representing a unique combination of intrinsic tumor stresses. Integrating dependency and stress perturbation transcriptomic data, we illuminated a network of genes with vital functions spanning diverse stress contexts. Analyses for central regulators of this network nominated C16orf72/HAPSTR1, an evolutionarily ancient gene critical for the fitness of cells reliant on multiple stress response pathways. We found that HAPSTR1 plays a pleiotropic role in cellular stress signaling, functioning to titrate various specialized cell-autonomous and paracrine stress response programs. This function, while dispensable to unstressed cells and nematodes, is essential for resilience in the presence of stressors ranging from DNA damage to starvation and proteotoxicity. Mechanistically, diverse stresses induce HAPSTR1, which encodes a protein expressed as two equally abundant isoforms. Perfectly conserved residues in a domain shared between HAPSTR1 isoforms mediate oligomerization and binding to the ubiquitin ligase HUWE1. We show that HUWE1 is a required cofactor for HAPSTR1 to control stress signaling and that, in turn, HUWE1 feeds back to ubiquitinate and destabilize HAPSTR1. Altogether, we propose that HAPSTR1 is a central rheostat in a network of pathways responsible for cellular adaptability, the modulation of which may have broad utility in human disease.
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42

Nisar, Haider, Memoona Khan, Qamar Un Nisa Chaudhry, Raheel Iftikhar, and Tariq Ghafoor. "Case report: A novel mutation in RTEL1 gene in dyskeratosis congenita." Frontiers in Oncology 13 (March 2, 2023). http://dx.doi.org/10.3389/fonc.2023.1098876.

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Dyskeratosis congenita (DKC), also known as Zinsser–Cole–Engman syndrome, is a telomeropathy typically presenting as a triad of leukoplakia, nail dystrophy, and reticular hyperpigmentation. Reported genetic mutations linked to DKC include DKC1, TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53/TCAB1, and RTEL1. Homozygous, compound heterozygous, and heterozygous mutations in RTEL1 (RTEL1, regulator of telomere elongation helicase 1) gene on chromosome 20q13 are known to cause autosomal dominant as well as recessive DKC. Pathogenic variants of RTEL1 gene in DKC patients include c.2288G>T (p. Gly763Val), c.3791G>A (p. Arg1264His), and RTEL p. Arg981Trp. We report a novel homozygous variant of RTEL1, transcript ID: ENST00000360203.11, exon 24, c.2060C>T (p.Ala687Val), in a patient of DKC presenting with leukoplakia, dystrophic nails, reticulate pigmentation, and positive family history of a similar phenotype. The novel variant, reported as a variant of uncertain significance, may therefore be considered diagnostic for DKC in a Pakistani population.
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43

Lee, Chanjae, Rachael M. Cox, Ophelia Papoulas, Amjad Horani, Kevin Drew, Caitlin C. Devitt, Steven L. Brody, Edward M. Marcotte, and John B. Wallingford. "Functional partitioning of a liquid-like organelle during assembly of axonemal dyneins." eLife 9 (December 2, 2020). http://dx.doi.org/10.7554/elife.58662.

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Ciliary motility is driven by axonemal dyneins that are assembled in the cytoplasm before deployment to cilia. Motile ciliopathy can result from defects in the dyneins themselves or from defects in factors required for their cytoplasmic pre-assembly. Recent work demonstrates that axonemal dyneins, their specific assembly factors, and broadly-acting chaperones are concentrated in liquid-like organelles in the cytoplasm called DynAPs (Dynein Axonemal Particles). Here, we use in vivo imaging in Xenopus to show that inner dynein arm (IDA) and outer dynein arm (ODA) subunits are partitioned into non-overlapping sub-regions within DynAPs. Using affinity- purification mass-spectrometry of in vivo interaction partners, we also identify novel partners for inner and outer dynein arms. Among these, we identify C16orf71/Daap1 as a novel axonemal dynein regulator. Daap1 interacts with ODA subunits, localizes specifically to the cytoplasm, is enriched in DynAPs, and is required for the deployment of ODAs to axonemes. Our work reveals a new complexity in the structure and function of a cell-type specific liquid-like organelle that is directly relevant to human genetic disease.
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Abolnezhadian, Farhad, and Sara Iranparast. "Identification of a Novel C16orf57 Mutation in Iranian Patient With Clericuzio-type Poikiloderma with Neutropenia (CPN): A Case Report." Iranian Journal of Allergy, Asthma and Immunology, September 4, 2019. http://dx.doi.org/10.18502/ijaai.v18i4.1424.

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Poikiloderma is a hereditary pathologic situation in which the appearance of skin rash is associated with epidermal atrophy, telangiectasia, and reticular dyspigmentation skin symptoms of poikiloderma are usually caused by sun damage. The main reason forpoikiloderma is unknown. We introduce a 14- month-old boy who referred to our center with a complaint of fever and cough. Furthermore, hepatosplenomegaly symptoms had been presented at the time of birth and were continuously observed at age one. He had transient thrombocytopenia when he was born due to his prematurity condition, which was resolved during Intravenous Immunoglobin (IVIG) treatment. Therefore, the presence of various mutation scan lead to distinct clinical symptoms. Immunohematologic abnormalities such as increased level of IgM and IgE antibodies, as well as increased C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR), have been reported. However, mutation of the C16orf57 gene was identified in this patient. We also introduced a new genetic mutation in a particular part of DNA sequence (NM_001195302: exon6: c.T703C) that leads to new clinical finding in PN.
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Tanaka, Akio, Fanny Morice-Picard, Didier Lacombe, Nikoletta Nagy, Michihiro Hide, Alain Taïeb, and John McGrath. "Identification of a homozygous deletion mutation in C16orf57 in a family with Clericuzio-type poikiloderma with neutropenia." American Journal of Medical Genetics Part A, 2010, n/a. http://dx.doi.org/10.1002/ajmg.a.33455.

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Pim, David, Justyna Broniarczyk, Abida Siddiqa, Paola Massimi, and Lawrence Banks. "Human Papillomavirus type 16 L2 recruits both retromer and retriever complexes during retrograde trafficking of the viral genome to the cell nucleus." Journal of Virology, November 11, 2020. http://dx.doi.org/10.1128/jvi.02068-20.

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Previous studies have identified an interaction between Human Papillomavirus L2 minor capsid protein and sorting nexins 17 and 27 (SNX17 and SNX27) during virus infection. Further studies show involvement of both retromer and retriever complexes in this process, since knockdown of proteins from either complex impairs infection. In this study, we show that HPV L2 and EdU-labelled pseudovirions colocalize with both retromer and retriever, with components of each complex being bound by L2 during infection. We also show that both sorting nexins may interact with either of the recycling complexes, but that the interaction between SNX17 and HPV16 L2 is not responsible for retriever recruitment during infection, instead being required for retromer recruitment. Further, we show that retriever recruitment most likely involves direct interaction between L2 and the C16orf62 subunit of retriever, in a similar manner to its interaction with the VPS35 subunit of retromer. IMPORTANCE Previous studies identified sorting nexins 17 and 27, as well as the retromer complex, as playing a role in HPV infection. This study shows that the newly-identified retriever complex also plays an important role and begins to shed light on how both sorting nexins contribute to retromer and retriever recruitment during the infection process.
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Cade, Brian E., Jiwon Lee, Tamar Sofer, Heming Wang, Man Zhang, Han Chen, Sina A. Gharib, et al. "Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program." Genome Medicine 13, no. 1 (August 26, 2021). http://dx.doi.org/10.1186/s13073-021-00917-8.

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Abstract Background Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. Methods The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. Results We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10−8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. Conclusions We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.
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Taylor, Laura W., John E. French, Zachary G. Robbins, and Leena A. Nylander-French. "Epigenetic Markers Are Associated With Differences in Isocyanate Biomarker Levels in Exposed Spray-Painters." Frontiers in Genetics 12 (July 14, 2021). http://dx.doi.org/10.3389/fgene.2021.700636.

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Abstract:
Isocyanates are respiratory and skin sensitizers that are one of the main causes of occupational asthma globally. Genetic and epigenetic markers are associated with isocyanate-induced asthma and, before asthma develops, we have shown that genetic polymorphisms are associated with variation in plasma and urine biomarker levels in exposed workers. Inter-individual epigenetic variance may also have a significant role in the observed biomarker variability following isocyanate exposure. Therefore, we determined the percent methylation for CpG islands from DNA extracted from mononuclear blood cells of 24 male spray-painters exposed to 1,6-hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate. Spray-painters’ personal inhalation and skin exposure to these compounds and the respective biomarker levels of 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) in their plasma and urine were measured during three repeated industrial hygiene monitoring visits. We controlled for inhalation exposure, skin exposure, age, smoking status, and ethnicity as covariates and performed an epigenome-wide association study (EWAS) using likelihood-ratio statistical modeling. We identified 38 CpG markers associated with differences in isocyanate biomarker levels (Bonferroni &lt; 0.05). Annotations for these markers included 18 genes: ALG1, ANKRD11, C16orf89, CHD7, COL27A, FUZ, FZD9, HMGN1, KRT6A, LEPR, MAPK10, MED25, NOSIP, PKD1, SNX19, UNC13A, UROS, and ZFHX3. We explored the functions of the genes that have been published in the literature and used GeneMANIA to investigate gene ontologies and predicted protein-interaction networks. The protein functions of the predicted networks include keratinocyte migration, cell–cell adhesions, calcium transport, neurotransmitter release, nitric oxide production, and apoptosis regulation. Many of the protein pathway functions overlap with previous findings on genetic markers associated with variability both in isocyanate biomarker levels and asthma susceptibility, which suggests there are overlapping protein pathways that contribute to both isocyanate toxicokinetics and toxicodynamics. These predicted protein networks can inform future research on the mechanism of allergic airway sensitization by isocyanates and aid in the development of mitigation strategies to better protect worker health.
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