Artículos de revistas: "GPATCH11"

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Benbarche, Salima, Jose Maria Bello Pineda, Laura Baquero Galvis, Bo Liu, Jeetayu Biswas, Eric Wang, K. Ashley Lyttle et al. "Synthetic Introns Identify the Novel RNA Splicing Factor GPATCH8 As Required for Mis-Splicing Induced By SF3B1 Mutations". Blood 142, Supplement 1 (28 de noviembre de 2023): 3. http://dx.doi.org/10.1182/blood-2023-179848.

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Disclosures Mutations in the core RNA splicing factor SF3B1 are common across MDS, CLL, and clonal hematopoiesis. Prior studies have elucidated that mutations in SF3B1 result in neomorphic widespread changes in splicing due to usage of aberrant intronic branchpoint nucleotides. However, the molecular basis by which mutant SF3B1 induces mis-splicing is not established and therapeutic means to correct mis-splicing due to mutant SF3B1 do not exist. Recently, the aberrant gain-of-function splicing activity of mutant SF3B1 was harnessed to regulate expression of proteins in a mutant selective manner using synthetic version of endogenous mRNA sequences uniquely recognized by mutant SF3B1. Here, we utilized this technology to engineer a synthetic intron derived from MAP3K7 that interrupts the coding sequence of the fluorescent protein mEmerald such that mutant SF3B1 produces lower mEmerald expression than SF3B1 wild-type (WT) cells (Fig.A). This fluorescent splicing reporter was then used to perform positive enrichment whole genome CRISPR screens to identify genes whose deletion corrects SF3B1 mutant aberrant splicing. GPATCH8 was the single most robust hit. GPATCH8 knockout strongly corrected mis-splicing of both synthetic and endogenous MAP3K7 introns (Fig.A). A previously unexplored protein, GPATCH8 has domains characteristic of RNA splicing factors including a G-patch motif, thought to be important in activating RNA helicases. Interestingly, recent work suggests that mutations in SF3B1 result in mis-splicing by disrupting physical interaction of SF3B1 to the RNA helicase DHX15 via the G-patch domain containing protein SUGP1. We therefore compared SUGP1 to GPATCH8 activity, evaluating first their transcriptome-wide binding sites using TRIBE-seq. We found that both proteins predominantly target intronic sequences over other genomic regions suggesting roles in splicing. RNA-seq of SF3B1 mutant and WT cells with or without GPATCH8/SUGP1 deletion revealed that ~33% of SF3B1 mutant splicing alterations are corrected by GPATCH8 deletion, while ~60% of SF3B1 mutant splicing alterations are recapitulated upon SUGP1 deletion. GPATCH8 regulated splicing events have stronger branchpoints indicating a potential role for GPATCH8 in 3' splice site recognition. To further understand the connection between GPATCH8 and mutant SF3B1, we performed mass spectrometry studies of immunoprecipitated endogenous GPATCH8 in SF3B1 WT and mutant knockin cells. This revealed strong interaction between GPATCH8 and DHX15. GPATCH8 interacts with DHX15 at the same sites previously shown to be occupied by SUGP1 in crystal structures of the SUGP1/DHX15 interaction. These data and further biochemical studies elucidated that GPATCH8 competes with SUGP1 for interaction to DHX15. As such, deletion of GPATCH8 corrects SF3B1 mutant mis-splicing by enhancing the interaction of SUGP1 and DHX15 to the mutant SF3b complex. Given that GPATCH8 is required for a large proportion of the splicing alterations induced by mutant SF3B1, we next evaluated the phenotypic effect of correcting SF3B1 mutant mis-splicing. We first tested the impact of anti-Gpatch8 shRNAs in bone marrow from WT mice as well as animals with conditional knockin of Sf3b1 K700E, K666N, or R625H mutations. While each Sf3b1 mutation results in impaired colony formation of hematopoietic precursors in methylcellulose assays, silencing of Gpatch8 rescued colony formation from hematopoietic precursors of each of the different Sf3b1 mutant mice and was tolerated by normal hematopoietic precursors (Fig.B). Moreover, while CRISPR base-edited knockin of the SF3B1 K700E mutation in adult CD34 + cells impaired erythroid development, this erythroid differentiation defect was rescued by GPATCH8 deletion in the same cells (Fig.B). These data identify GPATCH8 as a novel RNA splicing factor involved in quality control of RNA branchpoint selection whose expression is required for mis-splicing by the different mutant forms of SF3B1. GPATCH8 antagonizes the activity of SUGP1 by competing for interaction with DHX15. These findings suggest that disrupting GPATCH8/DHX15 interaction could have important therapeutic benefit for the multitude of SF3B1 mutant hematopoietic diseases. This study also demonstrates the power of synthetic intronic splicing assays for discovery of trans factors and druggable proteins required by leukemia-associated mutant RNA splicing factors. Abdel-Wahab: AbbVie, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Loxo/Lilly: Consultancy; Nurix Therapeutics: Research Funding; Minovia Therapeutics: Research Funding; Amphista Therapeutics: Consultancy; AstraZeneca: Consultancy; Harmonic Discovery: Current holder of stock options in a privately-held company. Figure 1

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Stern, Edward P., Sandra G. Guerra, Harry Chinque, Vanessa Acquaah, David González-Serna, Markella Ponticos, Javier Martin et al. "Analysis of Anti-RNA Polymerase III Antibody-positive Systemic Sclerosis and Altered GPATCH2L and CTNND2 Expression in Scleroderma Renal Crisis". Journal of Rheumatology 47, n.º 11 (15 de marzo de 2020): 1668–77. http://dx.doi.org/10.3899/jrheum.190945.

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ObjectiveScleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti-RNA polymerase III antibody (ARA) autoantibodies. We investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with SRC.MethodsARA-positive patients (n = 99) with at least 5 years’ follow-up (49% with a history of SRC) were selected from a well characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort.ResultsAnalysis of 641,489 SNP suggested association of POU2F1 (rs2093658; P = 1.98 × 10−5), CTNND2 (rs1859082; P = 5.58 × 10−5), HECW2 (rs16849716; P = 1.2 × 10−4), and GPATCH2L (rs935332; P = 4.92 × 10−5) with SRC. Further, the validation cohort showed an association between rs935332 within the GPATCH2L region, with SRC (P = 0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L (P = 0.026) and glomerular expression of CTNND2 (P = 0.026) in SRC samples (n = 8) compared with normal human kidney controls (n = 8), despite absence of any genetic replication for the associated SNP.ConclusionIncreased expression of 2 candidate proteins, GPATCH2L and CTNND2, in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L, this may reflect genetic susceptibility in ARA-positive patients with SSc based upon 2 independent cohorts.

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Chapman, Ria M., Caroline L. Tinsley, Matthew J. Hill, Marc P. Forrest, Katherine E. Tansey, Antonio F. Pardiñas, Elliott Rees et al. "Convergent Evidence That ZNF804A Is a Regulator of Pre-messenger RNA Processing and Gene Expression". Schizophrenia Bulletin 45, n.º 6 (29 de diciembre de 2018): 1267–78. http://dx.doi.org/10.1093/schbul/sby183.

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Abstract Genome-wide association studies have linked common variation in ZNF804A with an increased risk of schizophrenia. However, little is known about the biology of ZNF804A and its role in schizophrenia. Here, we investigate the function of ZNF804A using a variety of complementary molecular techniques. We show that ZNF804A is a nuclear protein that interacts with neuronal RNA splicing factors and RNA-binding proteins including RBFOX1, which is also associated with schizophrenia, CELF3/4, components of the ubiquitin-proteasome system and the ZNF804A paralog, GPATCH8. GPATCH8 also interacts with splicing factors and is localized to nuclear speckles indicative of a role in pre-messenger RNA (mRNA) processing. Sequence analysis showed that GPATCH8 contains ultraconserved, alternatively spliced poison exons that are also regulated by RBFOX proteins. ZNF804A knockdown in SH-SY5Y cells resulted in robust changes in gene expression and pre-mRNA splicing converging on pathways associated with nervous system development, synaptic contact, and cell adhesion. We observed enrichment (P = 1.66 × 10–9) for differentially spliced genes in ZNF804A-depleted cells among genes that contain RBFOX-dependent alternatively spliced exons. Differentially spliced genes in ZNF804A-depleted cells were also enriched for genes harboring de novo loss of function mutations in autism spectrum disorder (P = 6.25 × 10–7, enrichment 2.16) and common variant alleles associated with schizophrenia (P = .014), bipolar disorder and schizophrenia (P = .003), and autism spectrum disorder (P = .005). These data suggest that ZNF804A and its paralogs may interact with neuronal-splicing factors and RNA-binding proteins to regulate the expression of a subset of synaptic and neurodevelopmental genes.

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Kaneko, Hiroshi, Hiroshi Kitoh, Tohru Matsuura, Akio Masuda, Mikako Ito, Monica Mottes, Frank Rauch, Naoki Ishiguro y Kinji Ohno. "Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8". Human Genetics 130, n.º 5 (19 de mayo de 2011): 671–83. http://dx.doi.org/10.1007/s00439-011-1006-9.

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Nie, Ying, Yong Ran, Hong-Yan Zhang, Zhe-Fu Huang, Zhao-Yi Pan, Su-Yun Wang y Yan-Yi Wang. "GPATCH3 negatively regulates RLR-mediated innate antiviral responses by disrupting the assembly of VISA signalosome". PLOS Pathogens 13, n.º 4 (17 de abril de 2017): e1006328. http://dx.doi.org/10.1371/journal.ppat.1006328.

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Košuth, Ján, Martina Farkašovská, Filip Mochnacký, Zuzana Daxnerová y Juraj Ševc. "Selection of Reliable Reference Genes for Analysis of Gene Expression in Spinal Cord during Rat Postnatal Development and after Injury". Brain Sciences 10, n.º 1 (20 de diciembre de 2019): 6. http://dx.doi.org/10.3390/brainsci10010006.

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In order to obtain unbiased results of target gene expression, selection of the most appropriate reference gene (RG) remains a key precondition. However, an experimental study focused on the validation of stably expressed RGs in the rat spinal cord (SC) during development or after spinal cord injury (SCI) is missing. In our study, we tested the stability of the expression of nine selected RGs in rat SC tissue during normal development (postnatal days 1–43, adulthood) and after minimal (mSCI) and contusion (cSCI) spinal cord injury. The following RGs were tested: common housekeeping genes of basal cell metabolism (Gapdh, Hprt1, Mapk6) and protein translation (Rpl29, Eef1a1, Eif2b2), as well as newly designed RGs (Gpatch1, Gorasp1, Cds2) selected according to the RefGenes tool of GeneVestigator. The stability of RGs was assessed by geNorm, NormFinder, and BestKeeper. All three applets favored Gapdh and Eef1a1 as the most stable genes in SC during development. In both models of SCI, Eif2b2 displayed the highest stability of expression, followed by Gapdh and Gorasp1/Hprt1 in cSCI, and Gapdh and Eef1a1 in the mSCI experiments. To verify our results, selected RGs were employed for normalization of the expression of genes with a clear biological context in the SC—Gfap and Slc1a3/Glast during postnatal development and Aif1/Iba1 and Cd68/Ed1 after SCI.

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Li, Meifeng, Changxin Liu, Xiaowen Xu, Yapeng Liu, Zeying Jiang, Yinping Li, Yangfeng Lv, Shina Lu, Chengyu Hu y Huiling Mao. "Grass carp (Ctenopharyngodon idella) GPATCH3 initiates IFN 1 expression via the activation of STING-IRF7 signal axis". Developmental & Comparative Immunology 112 (noviembre de 2020): 103781. http://dx.doi.org/10.1016/j.dci.2020.103781.

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Rasevic, Nikola, Joseph Bastasic, Michele Rubini, Mohan R. Rakesh, Kelly M. Burkett, Debashree Ray, Peter A. Mossey et al. "Maternal and Parent-of-Origin Gene–Environment Effects on the Etiology of Orofacial Clefting". Genes 16, n.º 2 (4 de febrero de 2025): 195. https://doi.org/10.3390/genes16020195.

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Background/Objectives: We investigated maternal and parent-of-origin (PoO) gene-environment interaction effects on the risk of nonsyndromic orofacial clefts for two maternal environmental factors: periconceptional smoking and folic acid supplementation. Methods: Genome-wide single nucleotide polymorphisms (SNPs) genotypes and TopMed-imputed genotypes were obtained for case-parent triads from the EUROCRAN and ITALCLEFT studies. Candidate regions were selected around target SNPs from a previous genome-wide association study, resulting in 12 (726 SNPs) and 11 regions (730 SNPs) for maternal and PoO effects, respectively. Log-linear models were used to analyze 404 case-parent triads and 40 case-parent dyads. p-values were combined across regions. Results: None of the interactions reached statistical significance after correction for the number of regions tested. Nominally significant (pooled p-values < 0.05) interactions pointed to regions in or close to genes LRRC7 (maternal gene-folate interaction), NCKAP5 (PoO-smoking interaction), and IFT43 and GPATCH2L (PoO-folate interaction). Conclusions: Our results suggested that the genetic effects in or around these genes were heightened under periconceptional exposure to tobacco or no folic acid supplementation. The involvement of these genes in orofacial cleft development, in conjunction with environmental exposures, should be further studied.

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Blotta, Simona, Pierfrancesco Tassone, Rao H. Prabhala, Piersandro Tagliaferri, David Cervi, Samir Amin, Jana Jakubikova et al. "Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance". Blood 114, n.º 15 (8 de octubre de 2009): 3276–84. http://dx.doi.org/10.1182/blood-2009-04-219436.

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Abstract The transformation from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is thought to be associated with changes in immune processes. We have therefore used serologic analysis of recombinant cDNA expression library to screen the sera of MGUS patients to identify tumor-associated antigens. A total of 10 antigens were identified, with specific antibody responses in MGUS. Responses appeared to be directed against intracellular proteins involved in cellular functions, such as apoptosis (SON, IFT57/HIPPI), DNA and RNA binding (ZNF292, GPATCH4), signal transduction regulators (AKAP11), transcriptional corepressor (IRF2BP2), developmental proteins (OFD1), and proteins of the ubiquitin-proteasome pathway (PSMC1). Importantly, the gene responsible for the oral-facial-digital type I syndrome (OFD1) had response in 6 of 29 (20.6%) MGUS patients but 0 of 11 newly diagnosed MM patients. Interestingly, 3 of 11 (27.2%) MM patients after autologous stem cell transplantations showed responses to OFD1. We have confirmed T-cell responses against OFD1 in MGUS and observed down-regulation of GLI1/PTCH1 and p-β-catenin after OFD1 knock-down with specific siRNA, suggesting its functional role in the regulation of Hh and Wnt pathways. These findings demonstrate OFD1 as an important immune target and highlight its possible role in signal transduction and tumorigenesis in MGUS and MM.

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Triwidodo, Hermanu y St Nurlaela Fauziah. "Pengaruh sinar bulan terhadap telur Spodoptera exigua (Hübner) (Lepidoptera: Noctuidae) pada lahan bawang merah". Jurnal Entomologi Indonesia 17, n.º 1 (29 de abril de 2020): 45. http://dx.doi.org/10.5994/jei.17.1.45.

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Spodoptera exigua (Hübner) are nocturnal insects and one of the important pests of shallot. The activities of nocturnal insects are influenced by the moonlight. The aim of this research is to analyze the effect of moonlight on oviposition behaviour: number of egg patches, number of eggs per patches and egg gpatches distribution pattern of S. exigua. The research was done on three shallot field at Brebes Regency, Central Java during the new, half and full moon. The sampling included observing the number of egg groups, the number of eggs per egg group, and egg groups distribution pattern of S. exigua on each observation plot. The egg groups distribution pattern of S. exigua based on Morisita index. The result of this research showed that the number of egg groups and the number of eggs per egg group always increased from the new, half, and full moon. In general, the egg groups distribution pattern of S. exigua were clustered on three moonlight conditions. High intensity of moonlight (full moon) was be able to increase the number of egg groups and the number of eggs per egg groups of S. exigua, its potentially cause more attacks.

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Wan, Hui, Tingting Liu y Yuanxiang Lin. "MicroRNA-362-3p Inhibits Glioma Growth by Targeting PAX3 and Regulating Wnt/Beta-Catenin Pathway". Journal of Biomaterials and Tissue Engineering 11, n.º 11 (1 de noviembre de 2021): 2109–14. http://dx.doi.org/10.1166/jbt.2021.2383.

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Glioma is the most common intracranial malignancy and has been recognized as one of the most invasive primary tumors. Although there have been many studies on its growth mechanism, the molecular mechanism for growth inhibition is still unclear. The aim of this study was to show that microRNA-362-3p inhibits glioma growth by targeting PAX3 and regulating Wnt/beta-catenin pathway. We collected platelets from 12 healthy controls and 8 patients with glioma from the GEO database for comparison. The ncRNA and transcription factors that regulate the module were predicted to reveal the mechanism of microRNA-362-3p through co-expression module analysis, enrichment analysis, and hypergeometric testing. Two functional modules were obtained by integrating potential pathogenic genes and co-expression analysis. GPATCH4 and MYOD1 genes were expressed differentially and had active regulatory roles in the dysfunction module; thus, they were identified as key genes for glioma growth. Next, we performed ncRNA pivot and transcription factors (TFs) especially about the pivot analysis. The results showed microRNA-362-3p gene interest that significantly regulated the dysfunction module. Therefore, we identified microRNA-362-3p as a dysfunctional molecule in the growth process of glioma. MicroRNA-362-3p could inhibit glioma growth by targeting PAX3 and regulating the Wnt/beta-catenin pathway. The inhibition of this pathway may be a new target for the treatment of glioma. This study improves our understanding of growth inhibition in glioma and provides reference values for the treatment of this disease.

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Sahoo, Dipak Kumar, Dana C. Borcherding, Lawrance Chandra, Albert E. Jergens, Todd Atherly, Agnes Bourgois-Mochel, N. Matthew Ellinwood et al. "Differential Transcriptomic Profiles Following Stimulation with Lipopolysaccharide in Intestinal Organoids from Dogs with Inflammatory Bowel Disease and Intestinal Mast Cell Tumor". Cancers 14, n.º 14 (20 de julio de 2022): 3525. http://dx.doi.org/10.3390/cancers14143525.

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Lipopolysaccharide (LPS) is associated with chronic intestinal inflammation and promotes intestinal cancer progression in the gut. While the interplay between LPS and intestinal immune cells has been well-characterized, little is known about LPS and the intestinal epithelium interactions. In this study, we explored the differential effects of LPS on proliferation and the transcriptome in 3D enteroids/colonoids obtained from dogs with naturally occurring gastrointestinal (GI) diseases including inflammatory bowel disease (IBD) and intestinal mast cell tumor. The study objective was to analyze the LPS-induced modulation of signaling pathways involving the intestinal epithelia and contributing to colorectal cancer development in the context of an inflammatory (IBD) or a tumor microenvironment. While LPS incubation resulted in a pro-cancer gene expression pattern and stimulated proliferation of IBD enteroids and colonoids, downregulation of several cancer-associated genes such as Gpatch4, SLC7A1, ATP13A2, and TEX45 was also observed in tumor enteroids. Genes participating in porphyrin metabolism (CP), nucleocytoplasmic transport (EEF1A1), arachidonic acid, and glutathione metabolism (GPX1) exhibited a similar pattern of altered expression between IBD enteroids and IBD colonoids following LPS stimulation. In contrast, genes involved in anion transport, transcription and translation, apoptotic processes, and regulation of adaptive immune responses showed the opposite expression patterns between IBD enteroids and colonoids following LPS treatment. In brief, the crosstalk between LPS/TLR4 signal transduction pathway and several metabolic pathways such as primary bile acid biosynthesis and secretion, peroxisome, renin–angiotensin system, glutathione metabolism, and arachidonic acid pathways may be important in driving chronic intestinal inflammation and intestinal carcinogenesis.

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Zhou, Bo, Leyan Ling, Bin Wang, Fei Yang, Mengdan Hou, Fan Liu, Yu Li, Hui Luo, Wenping He y Hua Ye. "Hepatopancreas Transcriptome Analysis of Spinibarbus sinensis to Reveal Different Growth-Related Genes". Genes 15, n.º 7 (19 de julio de 2024): 949. http://dx.doi.org/10.3390/genes15070949.

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Spinibarbus sinensis, also known as Qingbo, is an important economic fish in China. However, the detailed mechanisms underlying its growth are still unknown. To excavate the genes and signaling pathways related to its growth, we compared the transcriptome profiles of the hepatopancreas tissues of S. sinensis, with two groups of growth rate for evaluation. An average of 66,304,909 and 68,739,585 clean reads were obtained in the fast growth (FG) and slow growth (SG) group, respectively. The differential gene expression analysis results showed that 272 differentially expressed genes (DEGs) were screened between the FG and SG groups, including 101 up-regulated genes and 171 down-regulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results showed that GO terms related to metabolic process, organic substance metabolic process, and catalytic activity were enriched, pathway signals related to steroid biosynthesis and protein digestion and absorption were also detected. Meanwhile, the potential key regulatory genes sst2, fndc4, and cckra related to the growth of S. sinensis were screened. Reverse transcript fluorescence quantitative PCR (RT-qPCR) validation of 18 DEGs associated with growth differences showed that the RT-qPCR results were consistent with RNA-seq analysis, and nine genes, stk31, gpr149, angptl1, fstl1, sik1, ror2, nlrc3, pdlim2, and nav2 were significantly expressed in the FG group. bmp1, stc1, gpatch8, sstrt2, s100a1, ktf6, cckar6, sync1, bhlha15, a total of nine genes were significantly expressed in the SG group. This study provides basic information for improving the growth characteristics of S. sinensis and the functional research of candidate genes.

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Rocio, Seniuk A., Agustina Sabater, Pablo Sanchis, Juan Bizzotto, Gastón Pascual, Estefania Labanca, Nicolas Anselmino et al. "Abstract 5648: Decoding the non-canonical functions of HO-1 in prostate cancer: A nuclear perspective and its association with a neuroendocrine signature". Cancer Research 84, n.º 6_Supplement (22 de marzo de 2024): 5648. http://dx.doi.org/10.1158/1538-7445.am2024-5648.

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Abstract Previous studies have demonstrated the non-canonical anti-tumor effect of heme-oxygenase 1 (HO-1) in prostate cancer (PCa). Although HO-1 is crucial for free heme degradation, its nuclear expression unveils non-canonical functions beyond its enzymatic function. Understanding the specifics of its non-canonical role remains a critical unmet need. In this study, we identified nuclear interactors of HO-1 and assessed their association with PCa.PCa cells were treated with hemin (80 µM, 24 h), a specific pharmacological inducer of HO-1. Nuclear HO-1 immunoprecipitation and LC-ESI MS/MS analysis identified 11 differential nuclear associated-HO-1 proteins between control and hemin-treated PCa cells (ILF3, ILF2, BCLAF1, SAFB, DDX17, SLC25A5, CASP14, PRDX1, BRIX1, CCDC175, and GPATCH1). Next, we performed an Ingenuity Pathway Analysis (QIAGEN) showing that ILF3 appears as a master regulator of this signature. To assess the clinical relevance of these factors in PCa, we analyzed overall survival (OS), progression-free survival (PFS), relapse free survival (RFS) in multiple PCa datasets (GSE34312, GSE35988, GSE3933, GSE46602, GSE6956, GSE70768, TCGA-PRAD, GSE70770, GSE16560, GSE24136; n=1064). We performed univariable and multivariable analyses for these factors and identified the ones that significantly and independently affected the OS, RFS, PFS. Next, a risk score model was built based on the expression of 9 genes (∑ni=1(Coefi×Expri)) for the GSE70770 dataset using these factors identifying a subpopulation of PCa patients with high-risk of RFS (HR: 7.39 High vs Low score, p<0.0001); ascertaining the critical role of this signature in PCa. To elucidate the association of these factors with the aggressive phenotype of PCa, we analyzed RNA-seq expression data from the MDA-PCa-PDXs series (PCa Patient Derived Xenografts Program; MD Anderson Cancer Center), capturing PCa heterogeneity. Unsupervised clustering analysis revealed that samples with high expression of HO-1 nuclear interactors corresponded to neuroendocrine tumors, negative for androgen receptor staining. Principal Component Analysis identified ILF3 as the most relevant HO-1 interactor driving PDXs’ samples variance, correlating with a significant decrease in relapse-free survival of PCa patients. Further, we used ChIP-Atlas to assess the epigenomic landscapes for these nuclear HO-1 interactors. Results indicated that 40% of HO-1 nuclear interactors were potential transcription regulators. Strikingly, KEGG pathways analyses revealed that their regulomes were significantly associated with neurodegenerative disorders, highlighting their relevance in neural processes. In conclusion, our findings suggest that HO-1 and its nuclear interactors may play a pivotal role in neuroendocrine PCa, shedding light on potential therapeutic targets for this aggressive form of the disease. Citation Format: Seniuk A. Rocio, Agustina Sabater, Pablo Sanchis, Juan Bizzotto, Gastón Pascual, Estefania Labanca, Nicolas Anselmino, Nora Navone, Elba Vazquez, Pia Valacco, Javier Cotignola, Ayelén Toro, Geraldine Gueron. Decoding the non-canonical functions of HO-1 in prostate cancer: A nuclear perspective and its association with a neuroendocrine signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5648.

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Zanetti, Andrea, Gwendal Dujardin, Lucas Fares-Taie, Jeanne Amiel, Jérôme E. Roger, Isabelle Audo, Matthieu P. Robert et al. "GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment". Nature Communications 15, n.º 1 (21 de noviembre de 2024). http://dx.doi.org/10.1038/s41467-024-54549-8.

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Dalseno, Destiny, Holly Anderton, Andrew Kueh, Marco J. Herold, John Silke, Andreas Strasser y Philippe Bouillet. "Deletion of Gpatch2 does not alter Tnf expression in mice". Cell Death & Disease 14, n.º 3 (27 de marzo de 2023). http://dx.doi.org/10.1038/s41419-023-05751-x.

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AbstractThe cytokine TNF has essential roles in immune defence against diverse pathogens and, when its expression is deregulated, it can drive severe inflammatory disease. The control of TNF levels is therefore critical for normal functioning of the immune system and health. We have identified GPATCH2 as a putative repressor of Tnf expression acting post-transcriptionally through the TNF 3’ UTR in a CRISPR screen for novel regulators of TNF. GPATCH2 is a proposed cancer-testis antigen with roles reported in proliferation in cell lines. However, its role in vivo has not been established. We have generated Gpatch2−/− mice on a C57BL/6 background to assess the potential of GPATCH2 as a regulator of Tnf expression. Here we provide the first insights into Gpatch2−/− animals and show that loss of GPATCH2 affects neither basal Tnf expression in mice, nor Tnf expression in intraperitoneal LPS and subcutaneous SMAC-mimetic injection models of inflammation. We detected GPATCH2 protein in mouse testis and at lower levels in several other tissues, however, the morphology of the testis and these other tissues appears normal in Gpatch2−/− animals. Gpatch2−/− mice are viable, appear grossly normal, and we did not detect notable aberrations in lymphoid tissues or blood cell composition. Collectively, our results suggest no discernible role of GPATCH2 in Tnf expression, and the absence of an overt phenotype in Gpatch2−/− mice warrants further investigation of the role of GPATCH2.

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Kanwal, Nidhi, Nicolai Krogh, Indira Memet, Nicolas Lemus-Diaz, Chairini C. Thomé, Luisa M. Welp, Athanasia Mizi et al. "GPATCH4 regulates rRNA and snRNA 2′-O-methylation in both DHX15-dependent and DHX15-independent manners". Nucleic Acids Research, 19 de diciembre de 2023. http://dx.doi.org/10.1093/nar/gkad1202.

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Abstract Regulation of RNA helicase activity, often accomplished by protein cofactors, is essential to ensure target specificity within the complex cellular environment. The largest family of RNA helicase cofactors are the G-patch proteins, but the cognate RNA helicases and cellular functions of numerous human G-patch proteins remain elusive. Here, we discover that GPATCH4 is a stimulatory cofactor of DHX15 that interacts with the DEAH box helicase in the nucleolus via residues in its G-patch domain. We reveal that GPATCH4 associates with pre-ribosomal particles, and crosslinks to the transcribed ribosomal DNA locus and precursor ribosomal RNAs as well as binding to small nucleolar- and small Cajal body-associated RNAs that guide rRNA and snRNA modifications. Loss of GPATCH4 impairs 2′-O-methylation at various rRNA and snRNA sites leading to decreased protein synthesis and cell growth. We demonstrate that the regulation of 2′-O-methylation by GPATCH4 is both dependent on, and independent of, its interaction with DHX15. Intriguingly, the ATPase activity of DHX15 is necessary for efficient methylation of DHX15-dependent sites, suggesting a function of DHX15 in regulating snoRNA-guided 2′-O-methylation of rRNA that requires activation by GPATCH4. Overall, our findings extend knowledge on RNA helicase regulation by G-patch proteins and also provide important new insights into the mechanisms regulating installation of rRNA and snRNA modifications, which are essential for ribosome function and pre-mRNA splicing.

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Li, Yi, Paulina Fischer, Mengjiao Wang, Qianxing Zhou, Aixia Song, Rui Yuan, Wanyu Meng et al. "Structural insights into spliceosome fidelity: DHX35–GPATCH1- mediated rejection of aberrant splicing substrates". Cell Research, 28 de febrero de 2025. https://doi.org/10.1038/s41422-025-01084-w.

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Abstract The spliceosome, a highly dynamic macromolecular assembly, catalyzes the precise removal of introns from pre-mRNAs. Recent studies have provided comprehensive structural insights into the step-wise assembly, catalytic splicing and final disassembly of the spliceosome. However, the molecular details of how the spliceosome recognizes and rejects suboptimal splicing substrates remained unclear. Here, we show cryo-electron microscopy structures of spliceosomal quality control complexes from a thermophilic eukaryote, Chaetomium thermophilum. The spliceosomes, henceforth termed B*Q, are stalled at a catalytically activated state but prior to the first splicing reaction due to an aberrant 5’ splice site conformation. This state is recognized by G-patch protein GPATCH1, which is docked onto PRP8-EN and -RH domains and has recruited the cognate DHX35 helicase to its U2 snRNA substrate. In B*Q, DHX35 has dissociated the U2/branch site helix, while the disassembly helicase DHX15 is docked close to its U6 RNA 3’-end substrate. Our work thus provides mechanistic insights into the concerted action of two spliceosomal helicases in maintaining splicing fidelity by priming spliceosomes that are bound to aberrant splice substrates for disassembly.

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19

Thummala, Sabitha, Sarah Fathima, Nithya Kruthi, Junaid Ahmed Khan Ghori, Katherine Saikia, Vivek Belde, Balamurali Andiyakkal Rajendran y Rahul Ranganathan. "Genetic Polymorphisms in RNF138, ABCA1 and ESRRG-GPATCH2 Genes and their Role in Insulin Resistance Risk among Normal BMI Individuals in Indian Population: A Case-control Study". JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH, 1 de enero de 2025. https://doi.org/10.7860/jcdr/2025/72551.20519.

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Introduction: India, characterised as the “diabetes capital” of the world, faces a rapidly increasing diabetes crisis, with over 65 million cases diagnosed. Despite the growing prevalence, the genetic underpinnings of Insulin Resistance (IR) among Indians with a normal Body Mass Index (BMI) remains understudied. Aim: To fill the knowledge gap by investigating the association of specific gene variants (RNF138, ABCA1, and Oestrogen-Related Receptor γ (ESRRG)-GPATCH2) with IR risk in this demographic. Materials and Methods: This study was a case-control study conducted in Bengaluru, Karnataka, India on a total of 191 participants (90 men and 101 women). The study, including data collection and analysis, was completed over a period of six months. Participants were categorised into cases (Homeostasis Model Assessment Insulin Resistance (HOMA2- IR) >2) and controls (HOMA2-IR <2) based on HOMA2-IR values. Genotyping for rs4799327 (RNF138), rs2275543 (ABCA1), and rs1497828 (ESRRG-GPATCH2) was performed using the Illumina Infinium Global Screening Array (GSA). Statistical analyses, including Odds Ratios (ORs), 95% Confidence Intervals (CIs), and inheritance model analysis, were conducted to assess the association between genotypes and IR. Results: Significant associations were found between IR and genetic variants rs4799327 (OR=2.74, 95% CI: 1.28-5.88, p-value=0.006) in RNF138, rs1497828 (OR=2.90, 95% CI: 1.51-5.57, p-value=0.0011) in ESRRG-GPATCH2 (dominant inheritance model), and rs2275543 (OR=3.50, 95% CI: 1.17- 10.42, p-value=0.011) in ABCA1 (additive model). The study highlights a notable susceptibility to IR linked to these genetic markers among individuals with a normal BMI in the Indian population. Conclusion: This study underscores the importance of genetic factors in the risk of developing IR among Indians with a normal BMI, suggesting a complex interplay of genetics beyond traditional risk factors. These findings necessitate further research into the functional significance of these associations and their potential implications for targeted interventions and preventive strategies in high-risk populations.

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20

Benbarche, Salima, Jose Mario Bello Pineda, Laura Baquero Galvis, Jeetayu Biswas, Bo Liu, Eric Wang, Qian Zhang et al. "GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies". Molecular Cell, abril de 2024. http://dx.doi.org/10.1016/j.molcel.2024.04.006.

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21

Kodera, Kazuki, Ryuichi Hishida, Akiko Sakai, Hiromi Nyuzuki, Noriko Matsui, Tomoyuki Yamanaka, Akihiko Saitoh y Hideaki Matsui. "GPATCH4 contributes to nucleolus morphology and its dysfunction impairs cell viability". Biochemical and Biophysical Research Communications, diciembre de 2023, 149384. http://dx.doi.org/10.1016/j.bbrc.2023.149384.

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22

Abudukeremu, Aikedaimu, Guliqiati Azatibieke, Gulisitan Yimiti, Yaqun Guan y Zhe Chen. "Development of Polyclonal Antibodies for the Preliminary Characterization of GPATCH1, a Novel Splicing Factor Associated with Human Osteoporosis". Applied Biochemistry and Biotechnology, 28 de noviembre de 2024. http://dx.doi.org/10.1007/s12010-024-05132-w.

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23

Tambi, Richa, Binte Ashraf, Sharon Nandkishore, Shermin Sharafat, Faiza Kader, Nasna Nassir, Nesrin Mohamed et al. "Single-Cell Reconstruction and Mutation Enrichment Analysis Identifies Dysregulated Cardiomyocyte and Endothelial Cells in Congenital Heart Disease". Physiological Genomics, 9 de octubre de 2023. http://dx.doi.org/10.1152/physiolgenomics.00070.2023.

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Congenital heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. To catalog the putative candidate CHD risk, we collected 16,349 variants (single nucleotide variants (SNVs) and Indels) impacting 8,308 genes in 3,166 CHD cases for a comprehensive meta-analysis. Using ACMG guidelines we excluded the 0.1% of benign/likely benign variants and resulting data set consisted of 83% predicted loss of function variants and 17% missense variants. Seventeen percent were de novo variants. A stepwise analysis identified 90 variant-enriched CHD genes, of which six ( GPATCH1, NYNRIN, TCLD2, CEP95, MAP3K19 and TTC36) were novel candidate CHD genes. Single cell transcriptome cluster reconstruction analysis on six CHD tissues and four controls revealed upregulation of top 10 frequently mutated genes primarily in cardiomyocytes. NOTCH1 (highest number of variants) and MYH6 (highest number of recurrent variants) expression was elevated in endocardial cells and cardiomyocytes, respectively, and 60% of these gene variants were associated with tetralogy of Fallot and coarctation of the aorta, respectively. Pseudobulk analysis using single cell transcriptome, revealed significant (p<0.05) upregulation of both NOTCH1 (endocardial cells) and MYH6 (cardiomyocytes) in the control heart data. We observed nine different subpopulations of CHD heart cardiomyocytes of which only four were observed in the control heart. This is the first comprehensive meta-analysis combining genomics and CHD single cell transcriptomics, identifying the most frequently mutated CHD genes, and demonstrating CHD gene heterogeneity, suggesting that multiple genes contribute to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.

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24

Bau, Da‐Tian, Ting‐Yuan Liu, Jai‐Sing Yang, William Tzu‐Liang Chen, Chia‐Wen Tsai, Wen‐Shin Chang, Tao‐Wei Ke et al. "Characterizing Genetic Susceptibility to Colorectal Cancer in Taiwan Through Genome‐Wide Association Study". Molecular Carcinogenesis, 11 de octubre de 2024. http://dx.doi.org/10.1002/mc.23823.

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ABSTRACTWe conducted the first genome‐wide association study (GWAS) of colorectal cancer (CRC) in Taiwan with 5342 cases and 61,015 controls. Ninety‐two SNPs in three genomic regions reached genome‐wide significance (p < 5 × 10−8). The lead SNPs in these three regions were: rs12778523 (OR = 1.18, 95% CI, 1.15–1.23, p = 4.51 × 10−13), an intergenic SNP between RNA5SP299 and LINC02676 at chromosome 10p14; rs647161 (OR = 1.14, 95% CI, 1.09–1.19, p = 2.21 × 10−9), an intronic SNP in PITX1 at 5q31.1, and rs10427139 (OR = 1.20, 95% CI, 1.14–1.28, p = 3.62 × 10−9), an intronic SNP in GPATCH1 at 19q13.1. We further validated CRC susceptibility SNPs previously identified through GWAS in other populations. A total of 61 CRC susceptibility SNPs were confirmed in Taiwanese. The top validated putative CRC susceptibility genes included: POU2AF2, HAO1, LAMC1, EIF3H, BMP2, ZMIZ1, BMP4, POLD3, CDKN1A, PREX1, CDKN2B, CDH1, and LRIG1. The top enriched pathways included TGF‐β signaling, BMP signaling, extracellular matrix organization, DNA repair, and cell cycle control. We could not validate SNPs in HLA‐G at 6p22.1 and in NOTCH4 at 6p21.32. We generated a weighted genetic risk score (GRS) using the 61 SNPs and constructed receiver operating characteristic (ROC) curves using the GRS to predict CRC. The area under the ROC curve (AUC) was 0.589 for GRS alone and 0.645 for GRS, sex, and age. These susceptibility SNPs and genes provide important insights into the molecular mechanisms of CRC development and help identify high‐risk individuals for CRC in Taiwan.

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Habimana, Richard, Kiplangat Ngeno, Tobias Otieno Okeno, Claire D’ andre Hirwa, Christian Keambou Tiambo y Nasser Kouadio Yao. "Genome-Wide Association Study of Growth Performance and Immune Response to Newcastle Disease Virus of Indigenous Chicken in Rwanda". Frontiers in Genetics 12 (16 de agosto de 2021). http://dx.doi.org/10.3389/fgene.2021.723980.

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A chicken genome has several regions with quantitative trait loci (QTLs). However, replication and confirmation of QTL effects are required particularly in African chicken populations. This study identified single nucleotide polymorphisms (SNPs) and putative genes responsible for body weight (BW) and antibody response (AbR) to Newcastle disease (ND) in Rwanda indigenous chicken (IC) using genome-wide association studies (GWAS). Multiple testing was corrected using chromosomal false detection rates of 5 and 10% for significant and suggestive thresholds, respectively. BioMart data mining and variant effect predictor tools were used to annotate SNPs and candidate genes, respectively. A total of four significant SNPs (rs74098018, rs13792572, rs314702374, and rs14123335) significantly (p ≤ 7.6E−5) associated with BW were identified on chromosomes (CHRs) 8, 11, and 19. In the vicinity of these SNPs, four genes such as pre-B-cell leukaemia homeobox 1 (PBX1), GPATCH1, MPHOSPH6, and MRM1 were identified. Four other significant SNPs (rs314787954, rs13623466, rs13910430, and rs737507850) all located on chromosome 1 were strongly (p ≤ 7.6E−5) associated with chicken antibody response to ND. The closest genes to these four SNPs were cell division cycle 16 (CDC16), zinc finger, BED-type containing 1 (ZBED1), myxovirus (influenza virus) resistance 1 (MX1), and growth factor receptor bound protein 2 (GRB2) related adaptor protein 2 (GRAP2). Besides, other SNPs and genes suggestively (p ≤ 1.5E−5) associated with BW and antibody response to ND were reported. This work offers a useful entry point for the discovery of causative genes accountable for essential QTLs regulating BW and antibody response to ND traits. Results provide auspicious genes and SNP-based markers that can be used in the improvement of growth performance and ND resistance in IC populations based on gene-based and/or marker-assisted breeding selection.

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26

Ferre-Fernández, Jesús-José, José-Daniel Aroca-Aguilar, Cristina Medina-Trillo, Juan-Manuel Bonet-Fernández, Carmen-Dora Méndez-Hernández, Laura Morales-Fernández, Marta Corton et al. "Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development". Scientific Reports 7, n.º 1 (11 de abril de 2017). http://dx.doi.org/10.1038/srep46175.

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Dou, Jinzhuang, Degang Wu, Lin Ding, Kai Wang, Minghui Jiang, Xiaoran Chai, Dermot F. Reilly et al. "Using off-target data from whole-exome sequencing to improve genotyping accuracy, association analysis and polygenic risk prediction". Briefings in Bioinformatics, 17 de junio de 2020. http://dx.doi.org/10.1093/bib/bbaa084.

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Abstract Whole-exome sequencing (WES) has been widely used to study the role of protein-coding variants in genetic diseases. Non-coding regions, typically covered by sparse off-target data, are often discarded by conventional WES analyses. Here, we develop a genotype calling pipeline named WEScall to analyse both target and off-target data. We leverage linkage disequilibrium shared within study samples and from an external reference panel to improve genotyping accuracy. In an application to WES of 2527 Chinese and Malays, WEScall can reduce the genotype discordance rate from 0.26% (SE= 6.4 × 10−6) to 0.08% (SE = 3.6 × 10−6) across 1.1 million single nucleotide polymorphisms (SNPs) in the deeply sequenced target regions. Furthermore, we obtain genotypes at 0.70% (SE = 3.0 × 10−6) discordance rate across 5.2 million off-target SNPs, which had ~1.2× mean sequencing depth. Using this dataset, we perform genome-wide association studies of 10 metabolic traits. Despite of our small sample size, we identify 10 loci at genome-wide significance (P < 5 × 10−8), including eight well-established loci. The two novel loci, both associated with glycated haemoglobin levels, are GPATCH8-SLC4A1 (rs369762319, P = 2.56 × 10−12) and ROR2 (rs1201042, P = 3.24 × 10−8). Finally, using summary statistics from UK Biobank and Biobank Japan, we show that polygenic risk prediction can be significantly improved for six out of nine traits by incorporating off-target data (P < 0.01). These results demonstrate WEScall as a useful tool to facilitate WES studies with decent amounts of off-target data.

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28

Roberson, Jeffrey L., Cyrus Farzaneh, Christopher J. Neylan, Renae Judy, Venexia Walker, Scott M. Damrauer, Michael G. Levin y Lillias H. Maguire. "Genome-Wide Association Study Identifies Genes for Hair Growth and Patterning are Associated With Pilonidal Disease". Diseases of the Colon & Rectum, 20 de junio de 2024. http://dx.doi.org/10.1097/dcr.0000000000003308.

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BACKGROUND: Pilonidal sinus disease is a highly morbid condition characterized by the formation of chronic sinus tracts throughout the sacrococcygeal region. Despite its commonality and strong association with family history, there is no prior investigation of genetic risk factors for pilonidal sinus disease. OBJECTIVE: To identify genetic risk factors for pilonidal sinus disease. DESIGN: Genome-wide association study. SETTINGS: The United Kingdom Biobank, FinnGen Biobank, and PennMedicine Biobank. PATIENTS: There were 772,072 participants. MAIN OUTCOME MEASURE: Genome-wide significant variants (p < 5x10 -8) were mapped to genes using physical distance and gene expression in skin. Genetic correlation between pilonidal sinus disease and morphometric, androgen-driven, and hair phenotypes was estimated with LD score regression. Finally, a genome-first approach to rare, predicted deleterious variants in hair shaft genes TCHH, PADI3, and TGM3 was conducted for association with pilonidal sinus disease via PennMedicine Biobank. RESULTS: Genome-wide association study comprised of 2,835 individuals with pilonidal sinus disease identified 5 genome-wide significant loci, prioritizing HDAC9, TBX15, WARS2, RP11-293M10.1, PRKAR1B, TWIST1, GPATCH2L, NEK9, and EIF2B2, as putative causal genes; several of these genes have known roles in balding and hair patterning. There was significant correlation between the genetic background of pilonidal sinus disease and that of the androgen-driven hair traits male pattern baldness and young age at first facial hair. In a candidate analysis of genes associated with syndromic hair disorders, rare coding variants in TCHH, a monogenic cause of uncombable hair syndrome, were associated with increased prevalence of pilonidal sinus disease (OR 4.81 [5% CI, 2.06-11.2]). LIMITATIONS: This study is limited to European ancestry. However, because there is a higher incidence of pilonidal sinus disease in men of European ancestry, this analysis is focused on the at-risk population CONCLUSION: Genetic analysis of pilonidal sinus disease identified shared genetic architecture with hair biology and androgen-driven traits. As the first study investigating the genetic basis of pilonidal sinus disease, this provides biological insight into the long-appreciated connection between the disease state, male gender, and hair. See Video abstract.

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29

Zhang, Siqi, Qikai Niu, Lin Tong, Sihong Liu, Pengqian Wang, Haiyu Xu, Bing Li y Huamin Zhang. "Identification of the susceptible genes and mechanism underlying the comorbid presence of coronary artery disease and rheumatoid arthritis: a network modularization analysis". BMC Genomics 24, n.º 1 (20 de julio de 2023). http://dx.doi.org/10.1186/s12864-023-09519-7.

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Abstract Objective The comorbidities of coronary artery disease (CAD) and rheumatoid arthritis (RA) are mutual risk factors, which lead to higher mortality, but the biological mechanisms connecting the two remain unclear. Here, we aimed to identify the risk genes for the comorbid presence of these two complex diseases using a network modularization approach, to offer insights into clinical therapy and drug development for these diseases. Method The expression profile data of patients CAD with and without RA were obtained from the GEO database (GSE110008). Based on the differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA) was used to construct a gene network, detect co-expression modules, and explore their relation to clinical traits. The Zsummary index, gene significance (GS), and module membership (MM) were utilized to screen the important differentiated modules and hub genes. The GO and KEGG pathway enrichment analysis were applied to analyze potential mechanisms. Result Based on the 278 DEGs obtained, 41 modules were identified, of which 17 and 24 modules were positively and negatively correlated with the comorbid occurrence of CAD and RA (CAD&RA), respectively. Thirteen modules with Zsummary < 2 were found to be the underlying modules, which may be related to CAD&RA. With GS ≥ 0.5 and MM ≥ 0.8, 49 hub genes were identified, such as ADO, ABCA11P, POT1, ZNF141, GPATCH8, ATF6 and MIA3, etc. The area under the curve values of the representative seven hub genes under the three models (LR, KNN, SVM) were greater than 0.88. Enrichment analysis revealed that the biological functions of the targeted modules were mainly involved in cAMP-dependent protein kinase activity, demethylase activity, regulation of calcium ion import, positive regulation of tyrosine, phosphorylation of STAT protein, and tissue migration, etc. Conclusion Thirteen characteristic modules and 49 susceptibility hub genes were identified, and their corresponding molecular functions may reflect the underlying mechanism of CAD&RA, hence providing insights into the development of clinical therapies against these diseases.

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