Mutations in SEPT9 Cause Hereditary Neuralgic Amyotrophy

Total Page:16

File Type:pdf, Size:1020Kb

Mutations in SEPT9 Cause Hereditary Neuralgic Amyotrophy BRIEF COMMUNICATIONS in most affected individuals within weeks to months. A more common Mutations in SEPT9 cause sporadic form of painful brachial plexus neuropathy, called Parsonage- Turner syndrome, is clinically indistinguishable from HNA. Attacks of hereditary neuralgic amyotrophy brachial plexus neuritis are often triggered by infections, immuniza- Gregor Kuhlenba¨umer1–3,13, Mark C Hannibal4,13, Eva Nelis3,13, tions, parturition or strenuous use of the affected limb. Inflammatory Anja Schirmacher1, Nathalie Verpoorten3, Jan Meuleman3,4, changes in the blood and brachial plexus have been shown, suggesting Giles D J Watts4, Els De Vriendt3, Peter Young1, involvement of the immune system. The relapsing-remitting course Florian Sto¨gbauer1, Hartmut Halfter1, Joy Irobi3, Dirk Goossens3, and the environmental triggering make HNA unique among the Jurgen Del-Favero3, Benjamin G Betz4, Hyun Hor1, inherited neuropathies and might render it a model for more common Gert Kurlemann5, Thomas D Bird6,7, Eila Airaksinen8, sporadic diseases like Parsonage-Turner and Guillain-Barre´ syndromes. Tarja Mononen9, Adolfo Pou Serradell10, Jose´ M Prats11, Dysmorphic features such as hypotelorism, epicanthal folds and, rarely, Christine Van Broeckhoven3, Peter De Jonghe3,12, cleft palate have been found in many but not all individuals with 1 Vincent Timmerman3,13, E Bernd Ringelstein1,2,13 & HNA . We previously assigned a major HNA locus to a 3.5-cM Phillip F Chance4,6,13 (1.8-Mb) candidate region on chromosome 17q25 and found evidence for a founder effect among some North American families2–5. Hereditary neuralgic amyotrophy (HNA) is an autosomal In this study, we included ten previously reported multigeneration dominant recurrent neuropathy affecting the brachial plexus. families with the classical HNA phenotype from different geographic HNA is triggered by environmental factors such as infection or origins (Table 1). The study was approved by the ethics committee of parturition. We report three mutations in the gene septin 9 the Universities of Antwerp, Mu¨nster and Seattle, and informed (SEPT9) in six families with HNA linked to chromosome 17q25. consent was obtained from all participants. All families showed linkage HNA is the first monogenetic disease caused by mutations in a to chromosome 17q25 (refs. 2–5). Segregation analysis of short gene of the septin family. Septins are implicated in formation tandem repeat (STR) markers in informative recombinants of these of the cytoskeleton, cell division and tumorigenesis. families allowed further reduction of the HNA locus to a B600-kb interval containing only two known genes, SEC14-like 1 (SEC14L1) HNA (OMIM162100) is an autosomal dominant peripheral neuro- and SEPT9 (Fig. 1a and Supplementary Fig. 1 and Supplementary pathy with a worldwide distribution1. The clinical hallmarks of HNA Table 1 online). In addition, we confirmed allele sharing over at least are recurrent painful brachial plexus neuropathies with weakness and 23 consecutive STRs between families K4004 and K4015 but disproved atrophy of arm muscles and sensory loss. Full or partial recovery occurs allele sharing between these families and family K4018, previously Table 1 Ethnic origin, genetic findings and presence of dysmorphic features Family HNA-2 HNA-5 HNA-8 HNA-9 K4000 K4003 K4004 K4007 K4015 K4018 Origin TU FI SP SP AE AE AE AE AE AE Allele sharing No No No No Yesa No Yesa Yesa Yesa No SEPT9 mutation À131G-C262C-T262C-T262C-TNone262C-T None None None 278C-T Amino acid substitution None, 5¢ UTR R88W R88W R88W – R88W – – – S93F Control individualsb 500 GE, 107 TU 500 GE, 100 AE, 500 GE, 100 AE, 500 GE, 100 AE, – 500 GE, 100 AE, – – – 500 GE, 100 AE 102 FI, 97 SP 102 FI, 97 SP 102 FI, 97 SP 102 FI, 97 SP Average age of onset (y) 17 13 15 11 15 19 9 16 17 12 Dysmorphic features Absent Present Present Present Present Present Present Present Present Present AE, North American of European descent; FI, Finnish; GE, German; SP, Spanish; TU, Turkish. aDetails regarding allele sharing are given in Supplementary Figure 2 and Supplementary Table 1 online. bNumber and ethnicity of control individuals in whom the respective mutation was absent. 1Department of Neurology and 2Leibniz Institute of Atherosclerosis Research, University of Mu¨ nster, Domagkstr. 3, D-48149 Mu¨ nster, Germany. 3Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium. 4Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA. 5Department of Pediatric Neurology, University of Mu¨ nster, Germany. 6Department of Neurology, University of Washington, Seattle, Washington, USA. 7Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA. 8Department of Paediatrics, University of Kuopio, Kuopio, Finland. 9Department of Clinical Genetics, Kuopio University Hospital, Kuopio, Finland. 10Department of Neurology, Hospital del Mar, Autonome University of Barcelona, Barcelona, Spain. 11Division of Child Neurology, Hospital de Cruces, Barakaldo, Basque Country, Spain. 12Division of Neurology, University Hospital, Antwerpen, Belgium. 13These authors contributed equally to this work. Correspondence should be addressed to G.K. ([email protected]). Received 3 May; accepted 3 August; published online 25 September 2005; doi:10.1038/ng1649 NATURE GENETICS ADVANCE ONLINE PUBLICATION 1 BRIEF COMMUNICATIONS a 1814 30185 39220 43043 61748 Sec14pen 263055 72GT1 MSF36296300240 MSFtriMSFpen345826D17S937 380058 408303 D17S939 GT1 509730 GT6 573707577194 617488622642 635606 CA5 SEC14L1 SEPT9 FM FM b SEPT9 Alternative exons 1a 2a 3a 4a 5a 6a 7a Exons 1 2 3 456789 1011 alpha zeta epsilon gamma beta c delta AK056495 Control Control K4003, HNA-5 HNA-2 HNA-8, HNA-9 K4018 –131G→C 262C→T 278C→T Protein Genomic DNA d R88W S93F Human Human Mouse Mouse Rat Rat Dog Dog Chicken Chicken Clawed frog Zebrafish Figure 1 Refined HNA candidate region, genomic organization of SEPT9, SEPT9 mutations in families with HNA and their conservation in different species. (a) The 600-kb HNA candidate region with locations of known and self-generated STR markers and genomic organization of SEC14L1 and SEPT9. FM, flanking marker. (b) Genomic organization of the different SEPT9 splice variants, including the reference cDNA SEPT9 alpha. Accession numbers of SEPT9 cDNAs are given in Supplementary Table 4 online. We numbered the exons of the SEPT9 alpha cDNA as exons 1–11 and all other exons according to their genomic location, adding the suffix ‘a’ to the exon number (1a–7a). (c) Sequence variants found in families with HNA. The –131G-C variant found in family HNA-2 is located in the 5¢ UTR of the SEPT9 alpha transcript. The 262C-T and the 278C-T transitions are located in exon 2 and lead to the amino acid changes R88W and S93F, respectively, in the N terminus of SEPT9. (d) Interspecies conservation of the untranslated –131G nucleotide at the genomic DNA level and of the R88 and S93 amino acid residues at the protein level. assumed to share alleles with families K4004 and K4015 based on a In the six families, the SEPT9 mutations were found in all four-marker haplotype5 (Supplementary Fig. 2 and Supplementary individuals with HNA. In a few families, nonpenetrance or Table 1 online). incomplete penetrance (indicated by the presence of dysmorphic We sequenced the coding region of SEPT9 including its untrans- facial features but absence of HNA attacks) occurred in individuals lated regions (UTRs), multiple splice variants and alternative first carrying a SEPT9 mutation. In four North American families exons (Fig. 1b and Supplementary Table 2 online). In four families with HNA, we could not detect a disease-associated mutation with HNA, we found a sequence variation (262C-T) in exon 2 of in SEPT9 (Table 1). But the affected individuals in these families SEPT9 (Table 1 and Fig. 1c). This transition causes the amino acid shared a disease-linked haplotype and can therefore be viewed as change R88W. These four families do not share a common disease- one large ancient family in which the mutation might be located associated haplotype, suggestive of a mutation hot spot rather than a in a region not covered by our mutation screen5. The STR founder mutation. The genomic variation did occur at a potential markers MSFtri–GT1 (Supplementary Table 1 online) located hypermutable CG dinucleotide. In family K4018, we detected a in SEPT9 did not show triple alleles or hemizygosity in the allele- transition (278C-T) leading to a S93F amino acid substitution sharing families, arguing against a large duplication or deletion. (Table 1 and Fig. 1c). In family HNA-2, we found a sequence Semiquantitative PCR analysis of exons 1–11 from genomic variation (À131G-C) in the 5¢ UTR of the SEPT9 alpha transcript DNA did not detect a duplication or deletion in families K4000, (Table 1 and Fig. 1c). None of the three sequence variants was found K4004, K4007 and K4015. In addition, PCR amplification and in ethnically matched control individuals (Table 1 and Supplemen- sequencing of somatic cell hybrids containing only the affected tary Table 3 online). All three mutation sites showed very high chromosome of affected individual K4000-47 showed no evidence interspecies conservation (Fig. 1d). for a deletion. 2 ADVANCE ONLINE PUBLICATION NATURE GENETICS BRIEF COMMUNICATIONS We analyzed the expression of mouse Sept9 in ventral horns (motor suggesting that it has a structural function in the cell10,11.Finally, neurons) and dorsal root ganglia (sensory neurons) of mouse embryos generalized overexpression of Sept9 was described in mouse models of at embryonic day 13 and found that Sept9 was expressed in both types human breast cancer and in human breast cancer cell lines, indicating of neurons (data not shown). that septin can also be involved in tumorigenesis12. We conclude that In an earlier mutation report of SEPT9,wedetectedtheR88W mutations in SEPT9 are a primary cause of HNA. mutation in a single family with HNA (HNA-8) but erroneously concluded that this mutation was a rare polymorphism6.Herewe Note: Supplementary information is available on the Nature Genetics website.
Recommended publications
  • 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.
    [Show full text]
  • Protein Kinase A-Mediated Septin7 Phosphorylation Disrupts Septin Filaments and Ciliogenesis
    cells Article Protein Kinase A-Mediated Septin7 Phosphorylation Disrupts Septin Filaments and Ciliogenesis Han-Yu Wang 1,2, Chun-Hsiang Lin 1, Yi-Ru Shen 1, Ting-Yu Chen 2,3, Chia-Yih Wang 2,3,* and Pao-Lin Kuo 1,2,4,* 1 Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; [email protected] (H.-Y.W.); [email protected] (C.-H.L.); [email protected] (Y.-R.S.) 2 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; [email protected] 3 Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan 4 Department of Obstetrics and Gynecology, National Cheng-Kung University Hospital, Tainan 704, Taiwan * Correspondence: [email protected] (C.-Y.W.); [email protected] (P.-L.K.); Tel.: +886-6-2353535 (ext. 5338); (C.-Y.W.)+886-6-2353535 (ext. 5262) (P.-L.K.) Abstract: Septins are GTP-binding proteins that form heteromeric filaments for proper cell growth and migration. Among the septins, septin7 (SEPT7) is an important component of all septin filaments. Here we show that protein kinase A (PKA) phosphorylates SEPT7 at Thr197, thus disrupting septin filament dynamics and ciliogenesis. The Thr197 residue of SEPT7, a PKA phosphorylating site, was conserved among different species. Treatment with cAMP or overexpression of PKA catalytic subunit (PKACA2) induced SEPT7 phosphorylation, followed by disruption of septin filament formation. Constitutive phosphorylation of SEPT7 at Thr197 reduced SEPT7-SEPT7 interaction, but did not affect SEPT7-SEPT6-SEPT2 or SEPT4 interaction.
    [Show full text]
  • A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans
    Journal of Personalized Medicine Article A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans Huichun Xu 1,* ID , Gerald W. Dorn II 2, Amol Shetty 3, Ankita Parihar 1, Tushar Dave 1, Shawn W. Robinson 4, Stephen S. Gottlieb 4 ID , Mark P. Donahue 5, Gordon F. Tomaselli 6, William E. Kraus 5,7 ID , Braxton D. Mitchell 1,8 and Stephen B. Liggett 9,* 1 Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [email protected] (A.P.); [email protected] (T.D.); [email protected] (B.D.M.) 2 Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; [email protected] 3 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [email protected] 4 Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [email protected] (S.W.R.); [email protected] (S.S.G.) 5 Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27708, USA; [email protected] (M.P.D.); [email protected] (W.E.K.) 6 Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD 21218, USA; [email protected] 7 Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA 8 Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration
    [Show full text]
  • A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
    Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase.
    [Show full text]
  • Global Analysis of O-Glcnac Glycoproteins in Activated Human T Cells Peder J
    Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells Peder J. Lund, Joshua E. Elias and Mark M. Davis This information is current as J Immunol 2016; 197:3086-3098; Prepublished online 21 of October 2, 2021. September 2016; doi: 10.4049/jimmunol.1502031 http://www.jimmunol.org/content/197/8/3086 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/09/20/jimmunol.150203 Material 1.DCSupplemental References This article cites 89 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/197/8/3086.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells Peder J.
    [Show full text]
  • Protein Symbol Protein Name Rank Metric Score 4F2 4F2 Cell-Surface
    Supplementary Table 2 Supplementary Table 2. Ranked list of proteins present in anti-Sema4D treated macrophage conditioned media obtained in the GSEA analysis of the proteomic data. Proteins are listed according to their rank metric score, which is the score used to position the gene in the ranked list of genes of the GSEA. Values are obtained from comparing Sema4D treated RAW conditioned media versus REST, which includes untreated, IgG treated and anti-Sema4D added RAW conditioned media. GSEA analysis was performed under standard conditions in November 2015. Protein Rank metric symbol Protein name score 4F2 4F2 cell-surface antigen heavy chain 2.5000 PLOD3 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 3 1.4815 ELOB Transcription elongation factor B polypeptide 2 1.4350 ARPC5 Actin-related protein 2/3 complex subunit 5 1.2603 OSTF1 teoclast-stimulating factor 1 1.2500 RL5 60S ribomal protein L5 1.2135 SYK Lysine--tRNA ligase 1.2135 RL10A 60S ribomal protein L10a 1.2135 TXNL1 Thioredoxin-like protein 1 1.1716 LIS1 Platelet-activating factor acetylhydrolase IB subunit alpha 1.1067 A4 Amyloid beta A4 protein 1.0911 H2B1M Histone H2B type 1-M 1.0514 UB2V2 Ubiquitin-conjugating enzyme E2 variant 2 1.0381 PDCD5 Programmed cell death protein 5 1.0373 UCHL3 Ubiquitin carboxyl-terminal hydrolase isozyme L3 1.0061 PLEC Plectin 1.0061 ITPA Inine triphphate pyrophphatase 0.9524 IF5A1 Eukaryotic translation initiation factor 5A-1 0.9314 ARP2 Actin-related protein 2 0.8618 HNRPL Heterogeneous nuclear ribonucleoprotein L 0.8576 DNJA3 DnaJ homolog subfamily
    [Show full text]
  • High Methylation of the SEPT9 Gene in Chinese Colorectal Cancer Patients
    High methylation of the SEPT9 gene in Chinese colorectal cancer patients X.L. Su1*, Y.F. Wang2*, S.J. Li3, F. Zhang4 and H.W. Cui1 1Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical University, Hohhot, China 2Department of Pathology, Inner Mongolia Medical University, Hohhot, China 3Department of Pathology, Chifeng Hospital, Chifeng, China 4Department of Pathology, Inner Mongolia People’s Hospital, Hohhot, China *These authors contributed equally to this study. Corresponding author: X.L. Su E-mail: [email protected] Genet. Mol. Res. 13 (2): 2513-2520 (2014) Received May 10, 2013 Accepted September 23, 2013 Published January 17, 2014 DOI http://dx.doi.org/10.4238/2014.January.17.5 ABSTRACT. Methylation of the septin 9 gene (SEPT9) occurs in higher frequency in colorectal cancer (CRC) compared to control samples, which suggests that SEPT9 methylation is a useful biomarker for screening CRC. However, the methylation status of SEPT9 in Chinese CRC patients is scarcely reported. In the present study, SEPT9 methylation was tested in CRC tissues obtained from a Chinese population and correlations with pathological characteristics were investigated. The methylation status of SEPT9 was detected using methylation-specific polymerase chain reaction (PCR)-denaturing high-performance liquid chromatography (MSP-DHPLC) in 234 colorectal tissues (172 cases, 62 controls). Samples were sequenced to confirm the results from MSP-DHPLC. The chi-squared test was used to analyze the correlation of SEPT9 gene methylation status and pathological characteristics in CRCs. SEPT9 gene methylation was detected in 152 of 172 (88.4%) cases of verified CRC and in 4 of 62 (6.5%) healthy controls (χ2 = 137.62, P < 0.001).
    [Show full text]
  • Methylated Sept9 Gene Is a Sensitive Biomarker for All Stages Of
    Review Article iMedPub Journals Colorectal Cancer: Open Access 2015 http://www.imedpub.com ISSN 2471-9943 Vol. 1 No. 1:2 DOI: 10.21767/2471-9943.100002 Methylated Sept9 Gene is a Sensitive Lele Song 1,2 and Yuemin Li1 Biomarker for all Stages of Colorectal Cancer 1 Department of Radiotherapy, the Chinese PLA 309 Hospital, No.17, Heishanhu Road, HaiDian District, Beijing 100091, P.R.China Abstract 2 BioChain (Beijing) Science and Technology, Inc, No.7A, Yongchang The SEPT9 gene methylation assay has been proved to be a reliable assay for CRC North Road, Economic and Technological detection by many studies. Due to the highly sensitive properties of the assay, Development Area, Beijing 100176, analysis of quantitative data is crucial for qualitative interpretation of the test P.R.China results. However, different analysis methods used currently in data interpretation led to variation in test sensitivity and may affect the test effectiveness in CRC detection. Here we review the methods used in data interpretation in major clinical Corresponding author: trials performed so far, and provide our recommendations for data interpretation in Lele Song future practice. [email protected] Keywords: Septin 9;SEPT9 , Septin; Methylation; Colorectal cancer; Adenoma; FOBT, FIT Department of Radiotherapy, the Chinese Received: October 11, 2015; Accepted: October 20, 2015; Published: October 27, 2015 PLA 309 Hospital, No.17, Heishanhu Road, HaiDian District, Beijing 100091, P.R.China. Introduction Tel: 86-13240149188 Colorectal cancer (CRC) has become the 3rd leading cause of new cancer cases in the United States in 2014[1]. The prevention of Citation: Song L, Li Y.
    [Show full text]
  • A Chromosome-Centric Human Proteome Project (C-HPP) To
    computational proteomics Laboratory for Computational Proteomics www.FenyoLab.org E-mail: [email protected] Facebook: NYUMC Computational Proteomics Laboratory Twitter: @CompProteomics Perspective pubs.acs.org/jpr A Chromosome-centric Human Proteome Project (C-HPP) to Characterize the Sets of Proteins Encoded in Chromosome 17 † ‡ § ∥ ‡ ⊥ Suli Liu, Hogune Im, Amos Bairoch, Massimo Cristofanilli, Rui Chen, Eric W. Deutsch, # ¶ △ ● § † Stephen Dalton, David Fenyo, Susan Fanayan,$ Chris Gates, , Pascale Gaudet, Marina Hincapie, ○ ■ △ ⬡ ‡ ⊥ ⬢ Samir Hanash, Hoguen Kim, Seul-Ki Jeong, Emma Lundberg, George Mias, Rajasree Menon, , ∥ □ △ # ⬡ ▲ † Zhaomei Mu, Edouard Nice, Young-Ki Paik, , Mathias Uhlen, Lance Wells, Shiaw-Lin Wu, † † † ‡ ⊥ ⬢ ⬡ Fangfei Yan, Fan Zhang, Yue Zhang, Michael Snyder, Gilbert S. Omenn, , Ronald C. Beavis, † # and William S. Hancock*, ,$, † Barnett Institute and Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States ‡ Stanford University, Palo Alto, California, United States § Swiss Institute of Bioinformatics (SIB) and University of Geneva, Geneva, Switzerland ∥ Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States ⊥ Institute for System Biology, Seattle, Washington, United States ¶ School of Medicine, New York University, New York, United States $Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia ○ MD Anderson Cancer Center, Houston, Texas, United States ■ Yonsei University College of Medicine, Yonsei University,
    [Show full text]
  • Structural Insight Into Filament Formation by Mammalian Septins
    doi:10.1038/nature06052 ARTICLES Structural insight into filament formation by mammalian septins Minhajuddin Sirajuddin1, Marian Farkasovsky1{, Florian Hauer2, Dorothee Ku¨hlmann1, Ian G. Macara3, Michael Weyand1, Holger Stark2 & Alfred Wittinghofer1 Septins are GTP-binding proteins that assemble into homo- and hetero-oligomers and filaments. Although they have key roles in various cellular processes, little is known concerning the structure of septin subunits or the organization and polarity of septin complexes. Here we present the structures of the human SEPT2 G domain and the heterotrimeric human SEPT2–SEPT6–SEPT7 complex. The structures reveal a universal bipolar polymer building block, composed of an extended G domain, which forms oligomers and filaments by conserved interactions between adjacent nucleotide-binding sites and/or the amino- and carboxy-terminal extensions. Unexpectedly, X-ray crystallography and electron microscopy showed that the predicted coiled coils are not involved in or required for complex and/or filament formation. The asymmetrical heterotrimers associate head-to-head to form a hexameric unit that is nonpolarized along the filament axis but is rotationally asymmetrical. The architecture of septin filaments differs fundamentally from that of other cytoskeletal structures. Septins are conserved GTP-binding proteins discovered in the bud- The SEPT2 G domain ding yeast Saccharomyces cerevisiae, where they organize into a ring at Human SEPT2 lacking 46 residues of the predicted C-terminal coiled the bud neck1–4. A parallel array of filaments is formed from hetero- coil (SEPT2-315) was isolated as recombinant protein from oligomers of four septins, which interact asymmetrically with other Escherichia coli. It contains 50% bound GDP and elutes in several proteins during cell division5,6.
    [Show full text]
  • Revised Subunit Order of Mammalian Septin Complexes Explains Their in Vitro Polymerization Properties Forooz Soroor1, 2, Moshe S
    bioRxiv preprint doi: https://doi.org/10.1101/569871; this version posted March 7, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Revised subunit order of mammalian septin complexes explains their in vitro polymerization properties Forooz Soroor1, 2, Moshe S. Kim1.2, Oliva Palander1, 2, Yadu Balachandran1, Richard Collins1, Samir Benlekbir3, John Rubinstein2,3 and William S. Trimble1,2,4,5 1Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8 2 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada, M5G 1A8 3Molecular Medicine Program, Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8 4Department of Physiology, University of Toronto, Toronto, Ontario, Canada, M5G 1A8 5Corresponding author ABSTRACT Septins are conserved GTP-binding cytoskeletal proteins that polymerize into filaments by end-to-end joining of heterooligomeric complexes. In human cells, both hexamers and octamers exist, and crystallography studies predicted the order of the hexamers to be SEPT7-SEPT6-SEPT2-SEPT2-SEPT6-SEPT7, while octamers are thought to have the same core, but with SEPT9 at the ends. However, based on this septin organization, octamers and hexamers would not be expected to co-polymerize due to incompatible ends. Here we isolated hexamers and octamers of specific composition from human cells and show that hexamers and octamers polymerize individually and, surprisingly, with each other. Binding of Borg3 results in distinctive clustering of each filament type.
    [Show full text]
  • Septin 9 I2 Is Downregulated in Tumors, Impairs Cancer Cell Migration and Alters Subnuclear Actin Filaments P
    Septin 9_i2 is downregulated in tumors, impairs cancer cell migration and alters subnuclear actin filaments P. Verdier-Pinard, D. Salaun, H. Bouguenina, S. Shimada, M. Pophillat, S. Audebert, E. Agavnian, S. Coslet, E. Charafe-Jauffret, T. Tachibana, et al. To cite this version: P. Verdier-Pinard, D. Salaun, H. Bouguenina, S. Shimada, M. Pophillat, et al.. Septin 9_i2 is down- regulated in tumors, impairs cancer cell migration and alters subnuclear actin filaments. Scientific Reports, Nature Publishing Group, 2017, 7, 10.1038/srep44976. hal-01787895 HAL Id: hal-01787895 https://hal.archives-ouvertes.fr/hal-01787895 Submitted on 7 May 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. www.nature.com/scientificreports OPEN Septin 9_i2 is downregulated in tumors, impairs cancer cell migration and alters subnuclear Received: 03 August 2016 Accepted: 20 February 2017 actin filaments Published: 24 March 2017 P. Verdier-Pinard1, D. Salaun1, H. Bouguenina1, S. Shimada2, M. Pophillat1, S. Audebert1, E. Agavnian1, S. Coslet1, E. Charafe-Jauffret1, T. Tachibana2 & A. Badache1 Functions of septin cytoskeletal polymers in tumorigenesis are still poorly defined. Their role in the regulation of cytokinesis and cell migration were proposed to contribute to cancer associated aneuploidy and metastasis.
    [Show full text]