Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase
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Novel Gene Fusions in Glioblastoma Tumor Tissue and Matched Patient Plasma
cancers Article Novel Gene Fusions in Glioblastoma Tumor Tissue and Matched Patient Plasma 1, 1, 1 1 1 Lan Wang y, Anudeep Yekula y, Koushik Muralidharan , Julia L. Small , Zachary S. Rosh , Keiko M. Kang 1,2, Bob S. Carter 1,* and Leonora Balaj 1,* 1 Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA; [email protected] (L.W.); [email protected] (A.Y.); [email protected] (K.M.); [email protected] (J.L.S.); [email protected] (Z.S.R.); [email protected] (K.M.K.) 2 School of Medicine, University of California San Diego, San Diego, CA 92092, USA * Correspondence: [email protected] (B.S.C.); [email protected] (L.B.) These authors contributed equally. y Received: 11 March 2020; Accepted: 7 May 2020; Published: 13 May 2020 Abstract: Sequencing studies have provided novel insights into the heterogeneous molecular landscape of glioblastoma (GBM), unveiling a subset of patients with gene fusions. Tissue biopsy is highly invasive, limited by sampling frequency and incompletely representative of intra-tumor heterogeneity. Extracellular vesicle-based liquid biopsy provides a minimally invasive alternative to diagnose and monitor tumor-specific molecular aberrations in patient biofluids. Here, we used targeted RNA sequencing to screen GBM tissue and the matched plasma of patients (n = 9) for RNA fusion transcripts. We identified two novel fusion transcripts in GBM tissue and five novel fusions in the matched plasma of GBM patients. The fusion transcripts FGFR3-TACC3 and VTI1A-TCF7L2 were detected in both tissue and matched plasma. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
RT² Profiler PCR Array (96-Well Format and 384-Well [4 X 96] Format)
RT² Profiler PCR Array (96-Well Format and 384-Well [4 x 96] Format) Human Mitochondria Cat. no. 330231 PAHS-087ZA For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 5700, 7000, 7300, 7500, Format A 7700, 7900HT, ViiA™ 7 (96-well block); Bio-Rad® models iCycler®, iQ™5, MyiQ™, MyiQ2; Bio-Rad/MJ Research Chromo4™; Eppendorf® Mastercycler® ep realplex models 2, 2s, 4, 4s; Stratagene® models Mx3005P®, Mx3000P®; Takara TP-800 RT² Profiler PCR Array, Applied Biosystems models 7500 (Fast block), 7900HT (Fast Format C block), StepOnePlus™, ViiA 7 (Fast block) RT² Profiler PCR Array, Bio-Rad CFX96™; Bio-Rad/MJ Research models DNA Format D Engine Opticon®, DNA Engine Opticon 2; Stratagene Mx4000® RT² Profiler PCR Array, Applied Biosystems models 7900HT (384-well block), ViiA 7 Format E (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (96-well block) Format F RT² Profiler PCR Array, Roche LightCycler 480 (384-well block) Format G RT² Profiler PCR Array, Fluidigm® BioMark™ Format H Sample & Assay Technologies Description The Human Mitochondria RT² Profiler PCR Array profiles the expression of 84 genes involved in the biogenesis and function of the cell's powerhouse organelle. The genes monitored by this array include regulators and mediators of mitochondrial molecular transport of not only the metabolites needed for the electron transport chain and oxidative phosphorylation, but also the ions required for maintaining the mitochondrial membrane polarization and potential important for ATP synthesis. Metabolism and energy production are not the only functions of mitochondria. -
Extending the Phenotypic Spectrum of Sengers Syndrome: Congenital Lactic Acidosis with Synthetic Liver Dysfunction
Himmelfarb Health Sciences Library, The George Washington University Health Sciences Research Commons Pathology Faculty Publications Pathology 4-13-2018 Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction. David B Beck Kristina Cusmano-Ozog George Washington University Nickie Andescavage George Washington University Eyby Leon George Washington University Follow this and additional works at: https://hsrc.himmelfarb.gwu.edu/smhs_path_facpubs Part of the Medical Pathology Commons, Pathology Commons, and the Translational Medical Research Commons APA Citation Beck, D., Cusmano-Ozog, K., Andescavage, N., & Leon, E. (2018). Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction.. Translational Science of Rare Diseases, 3 (1). http://dx.doi.org/10.3233/ TRD-180020 This Journal Article is brought to you for free and open access by the Pathology at Health Sciences Research Commons. It has been accepted for inclusion in Pathology Faculty Publications by an authorized administrator of Health Sciences Research Commons. For more information, please contact [email protected]. Translational Science of Rare Diseases 3 (2018) 45–48 45 DOI 10.3233/TRD-180020 IOS Press Original Research Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction David B. Becka, Kristina Cusmano-Ozogb, Nickie Andescavagec and Eyby Leonb,∗ aNational Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA bChildren’s National Health System, Rare Disease Institute, Genetics and Metabolism, Washington, DC, USA cChildren’s National Health System, Pediatrics, Neonatology, Washington, DC, USA Abstract. Sengers syndrome is a rare autosomal recessive mitochondrial disease characterized by lactic acidosis, hypertrophic cardiomyopathy and bilateral cataracts. -
Two Novel Mutations in the AGK Gene: Two Case Reports with Sengers
Techno e lo Kor et al., Gene Technol 2016, 5:1 n g e y G Gene Technology DOI: 10.4172/2329-6682.1000140 ISSN: 2329-6682 Case Report Open Access Two Novel Mutations in the AGK Gene: Two Case Reports with Sengers Syndrome Deniz Kor1*, Berna Seker Yılmaz1, Ozden Ozgur Horoz2, Gulay Ceylaner3, Selcuk Sızmaz4, Fadli Demir2 and Neslihan Onenli Mungan1 1Department of Pediatric Metabolism and Nutrition, Faculty of Medicine, Cukurova University, Adana, Turkey 2Department of Pediatrics, Faculty of Medicine, Cukurova University, Adana, Turkey 3Intergen Genetic Laboratory, Ankara, Turkey 4Department of Ophthalmology, Cukurova University Faculty of Medicine, Adana, Turkey Abstract Mutations in the AGK gene are known to cause Sengers Syndrome, a rare recessive disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance and lactic acidosis with normal mental development. Since the first report in 1975 by Sengers et al. about 50 individuals have been described as having this syndrome. Here we report two novel mutations in the AGK gene in two patients with neonatal Sengers syndrome. Keywords: AGK gene; Sengers syndrome; Cardiomyopathy; acylcarnitine levels, plasma amino acids and urine organic acids) Myopathy; Cataract were within normal limits except elevated levels of creatine kinases and lactate. Echocardiographic evaluation documented hypertrophic Introduction cardiomyopathy with an ejection fraction of 30%. Electromyography Sengers Syndrome (OMIM 212350), also known as cardiomyopathic and cerebral MRI showed no abnormality. A quadriceps muscle biopsy mitochondrial DNA depletion syndrome-10 (MTDPS10) is a rare revealed fatty infiltrations in the muscle fibers and myopathic changes. autosomal-recessive disorder characterized by congenital cataracts, Based on these observations a clinical diagnosis of Sengers Syndrome hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance was made. -
PAM16 (NM 016069) Human Recombinant Protein Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TP302828 PAM16 (NM_016069) Human Recombinant Protein Product data: Product Type: Recombinant Proteins Description: Recombinant protein of humanmitochondria-associated protein involved in granulocyte- macrophage colony-stimulating factor signal transduction (Magmas), nuclear gene encoding mitochondrial Species: Human Expression Host: HEK293T Tag: C-Myc/DDK Predicted MW: 13.6 kDa Concentration: >50 ug/mL as determined by microplate BCA method Purity: > 80% as determined by SDS-PAGE and Coomassie blue staining Buffer: 25 mM Tris.HCl, pH 7.3, 100 mM glycine, 10% glycerol Preparation: Recombinant protein was captured through anti-DDK affinity column followed by conventional chromatography steps. Storage: Store at -80°C. Stability: Stable for 12 months from the date of receipt of the product under proper storage and handling conditions. Avoid repeated freeze-thaw cycles. RefSeq: NP_057153 Locus ID: 51025 UniProt ID: Q9Y3D7 RefSeq Size: 600 Cytogenetics: 16p13.3 RefSeq ORF: 375 Synonyms: CGI-136; MAGMAS; SMDMDM; TIM16; TIMM16 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 PAM16 (NM_016069) Human Recombinant Protein – TP302828 Summary: This gene encodes a mitochondrial protein involved in granulocyte-macrophage colony- stimulating factor (GM-CSF) signaling. This protein also plays a role in the import of nuclear- encoded mitochondrial proteins into the mitochondrial matrix and may be important in reactive oxygen species (ROS) homeostasis. -
Supplemental Information
Supplemental information Dissection of the genomic structure of the miR-183/96/182 gene. Previously, we showed that the miR-183/96/182 cluster is an intergenic miRNA cluster, located in a ~60-kb interval between the genes encoding nuclear respiratory factor-1 (Nrf1) and ubiquitin-conjugating enzyme E2H (Ube2h) on mouse chr6qA3.3 (1). To start to uncover the genomic structure of the miR- 183/96/182 gene, we first studied genomic features around miR-183/96/182 in the UCSC genome browser (http://genome.UCSC.edu/), and identified two CpG islands 3.4-6.5 kb 5’ of pre-miR-183, the most 5’ miRNA of the cluster (Fig. 1A; Fig. S1 and Seq. S1). A cDNA clone, AK044220, located at 3.2-4.6 kb 5’ to pre-miR-183, encompasses the second CpG island (Fig. 1A; Fig. S1). We hypothesized that this cDNA clone was derived from 5’ exon(s) of the primary transcript of the miR-183/96/182 gene, as CpG islands are often associated with promoters (2). Supporting this hypothesis, multiple expressed sequences detected by gene-trap clones, including clone D016D06 (3, 4), were co-localized with the cDNA clone AK044220 (Fig. 1A; Fig. S1). Clone D016D06, deposited by the German GeneTrap Consortium (GGTC) (http://tikus.gsf.de) (3, 4), was derived from insertion of a retroviral construct, rFlpROSAβgeo in 129S2 ES cells (Fig. 1A and C). The rFlpROSAβgeo construct carries a promoterless reporter gene, the β−geo cassette - an in-frame fusion of the β-galactosidase and neomycin resistance (Neor) gene (5), with a splicing acceptor (SA) immediately upstream, and a polyA signal downstream of the β−geo cassette (Fig. -
Identification of Kinase Fusion Oncogenes in Post-Chernobyl Radiation-Induced Thyroid Cancers
Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers Julio C. Ricarte-Filho, … , Christopher E. Mason, James A. Fagin J Clin Invest. 2013;123(11):4935-4944. https://doi.org/10.1172/JCI69766. Research Article Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We examined tissues from 26 Ukrainian patients with thyroid cancer who were younger than 10 years of age and living in contaminated areas during the time of the Chernobyl nuclear reactor accident. We identified nonoverlapping somatic driver mutations in all 26 cases through candidate gene assays and next-generation RNA sequencing. We found that 22 tumors harbored fusion oncogenes that arose primarily through intrachromosomal rearrangements. Altogether, 23 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the 2 somatic rearrangements resulting in fusion of transcription factor ETS variant 6 (ETV6) with neurotrophic tyrosine kinase receptor, type 3 (NTRK3) and fusion of acylglycerol kinase (AGK) with BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. Fusion oncogenes were less prevalent in tumors from a cohort of children with pediatric thyroid cancers that had not been exposed to radiation but were from the same geographical regions. Radiation-induced thyroid cancers provide a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program. Find the latest version: https://jci.me/69766/pdf Related Commentary, page 4566 Research article Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers Julio C. -
Supplementary Materials
Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine -
Association of Imputed Prostate Cancer Transcriptome with Disease Risk Reveals Novel Mechanisms
Corrected: Author Correction ARTICLE https://doi.org/10.1038/s41467-019-10808-7 OPEN Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms Nima C. Emami1,2, Linda Kachuri2, Travis J. Meyers2, Rajdeep Das3,4, Joshua D. Hoffman2, Thomas J. Hoffmann 2,5, Donglei Hu 5,6,7, Jun Shan8, Felix Y. Feng3,4,7, Elad Ziv5,6,7, Stephen K. Van Den Eeden 3,8 & John S. Witte1,2,3,5,7 1234567890():,; Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes. 1 Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA 94158, USA. -
Role of Magmas in Protein Transport and Human Mitochondria Biogenesis
Human Molecular Genetics, 2010, Vol. 19, No. 7 1248–1262 doi:10.1093/hmg/ddq002 Advance Access published on January 6, 2010 Role of Magmas in protein transport and human mitochondria biogenesis Devanjan Sinha, Neha Joshi, Balasubramanyam Chittoor, Priyanka Samji and Patrick D’Silvaà Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka 560012, India Received December 1, 2009; Revised and Accepted January 3, 2010 Downloaded from Magmas, a conserved mammalian protein essential for eukaryotic development, is overexpressed in prostate carcinomas and cells exposed to granulocyte-macrophage colony-stimulating factor (GM-CSF). Reduced Magmas expression resulted in decreased proliferative rates in cultured cells. However, the cellular function of Magmas is still elusive. In this report, we have showed that human Magmas is an ortholog of Saccharomyces cerevisiae Pam16 having similar functions and is critical for protein translocation across http://hmg.oxfordjournals.org/ mitochondrial inner membrane. Human Magmas shows a complete growth complementation of Dpam16 yeast cells at all temperatures. On the basis of our analysis, we report that Magmas localizes into mitochon- dria and is peripherally associated with inner mitochondrial membrane in yeast and humans. Magmas forms a stable subcomplex with J-protein Pam18 or DnaJC19 through its C-terminal region and is tethered to TIM23 complex of yeast and humans. Importantly, amino acid alterations in Magmas leads to reduced stability of the subcomplex with Pam18 that results in temperature sensitivity and in vivo protein translocation defects in yeast cells. These observations highlight the central role of Magmas in protein import and mitochondria bio- genesis. In humans, absence of a functional DnaJC19 leads to dilated cardiac myophathic syndrome (DCM), a at Purdue University Libraries ADMN on January 18, 2015 genetic disorder with characteristic features of cardiac myophathy and neurodegeneration. -
Molecular Analyses of Malignant Pleural Mesothelioma
Molecular Analyses of Malignant Pleural Mesothelioma Shir Kiong Lo National Heart and Lung Institute Imperial College Dovehouse Street London SW3 6LY A thesis submitted for MD (Res) Faculty of Medicine, Imperial College London 2016 1 Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer that is strongly associated with asbestos exposure. Majority of patients with MPM present with advanced disease and the treatment paradigm mainly involves palliative chemotherapy and best supportive care. The current chemotherapy options are limited and ineffective hence there is an urgent need to improve patient outcomes. This requires better understanding of the genetic alterations driving MPM to improve diagnostic, prognostic and therapeutic strategies. This research aims to gain further insights in the pathogenesis of MPM by exploring the tumour transcriptional and mutational profiles. We compared gene expression profiles of 25 MPM tumours and 5 non-malignant pleura. This revealed differentially expressed genes involved in cell migration, invasion, cell cycle and the immune system that contribute to the malignant phenotype of MPM. We then constructed MPM-associated co-expression networks using weighted gene correlation network analysis to identify clusters of highly correlated genes. These identified three distinct molecular subtypes of MPM associated with genes involved in WNT and TGF-ß signalling pathways. Our results also revealed genes involved in cell cycle control especially the mitotic phase correlated significantly with poor prognosis. Through exome analysis of seven paired tumour/blood and 29 tumour samples, we identified frequent mutations in BAP1 and NF2. Additionally, the mutational profile of MPM is enriched with genes encoding FAK, MAPK and WNT signalling pathways.