DOCSLIB.ORG

A Combined Linkage and Exome Sequencing Analysis for Electrocardiogram Parameters in the Erasmus Rucphen Family Study

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

fgene-07-00190 November 4, 2016 Time: 17:11 # 1 ORIGINAL RESEARCH published: 08 November 2016 doi: 10.3389/fgene.2016.00190 A Combined Linkage and Exome Sequencing Analysis for Electrocardiogram Parameters in the Erasmus Rucphen Family Study Claudia T. Silva1,2,3, Irina V. Zorkoltseva4, Najaf Amin1, Ay ¸seDemirkan1,5, Elisabeth M. van Leeuwen1, Jan A. Kors6, Marten van den Berg6, Bruno H. Stricker7,8,9, André G. Uitterlinden8, Anatoly V. Kirichenko4, Jacqueline C. M. Witteman7, Rob Willemsen10, Ben A. Oostra1,11, Tatiana I. Axenovich4, Cornelia M. van Duijn1,11† and Aaron Isaacs1,11*† 1 Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands, Edited by: 2 Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá, Colombia, 3 GENIUROS Group, Genetics and Gudrun A. Brockmann, Genomics Research Center CIGGUR, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia, Humboldt University of Berlin, 4 Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia, 5 Department of Germany Human Genetics, Leiden University Medical Center, Leiden, Netherlands, 6 Department of Medical Informatics, Erasmus Reviewed by: University Medical Center, Rotterdam, Netherlands, 7 Department of Epidemiology, Erasmus University Medical Center, Catherine Stein, Rotterdam, Netherlands, 8 Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands, Case Western Reserve University, 9 Inspectorate of Health Care, The Hague, Netherlands, 10 Department of Clinical Genetics, Erasmus University Medical USA Center, Rotterdam, Netherlands, 11 Center for Medical Systems Biology, Leiden, Netherlands Anke Hinney, University of Duisburg-Essen, Germany Electrocardiogram (ECG) measurements play a key role in the diagnosis and prediction *Correspondence: of cardiac arrhythmias and sudden cardiac death. ECG parameters, such as the PR, Aaron Isaacs QRS, and QT intervals, are known to be heritable and genome-wide association studies [email protected] of these phenotypes have been successful in identifying common variants; however, †These authors have contributed equally to this work. a large proportion of the genetic variability of these traits remains to be elucidated. The aim of this study was to discover loci potentially harboring rare variants utilizing Specialty section: variance component linkage analysis in 1547 individuals from a large family-based study, This article was submitted to Applied Genetic Epidemiology, the Erasmus Rucphen Family Study (ERF). Linked regions were further explored using a section of the journal exome sequencing. Five suggestive linkage peaks were identified: two for QT interval Frontiers in Genetics (1q24, LOD D 2.63; 2q34, LOD D 2.05), one for QRS interval (1p35, LOD D 2.52) Received: 02 June 2016 and two for PR interval (9p22, LOD D 2.20; 14q11, LOD D 2.29). Fine-mapping using Accepted: 11 October 2016 Published: 08 November 2016 exome sequence data identified a C > G missense variant (c.713C > G, p.Ser238Cys) −4 Citation: in the FCRL2 gene associated with QT (rs74608430; P D 2.8 × 10 , minor allele Silva CT, Zorkoltseva IV, Amin N, frequency D 0.019). Heritability analysis demonstrated that the SNP explained 2.42% of Demirkan A, van Leeuwen EM, Kors JA, van den Berg M, the trait’s genetic variability in ERF (P D 0.02). Pathway analysis suggested that the gene Stricker BH, Uitterlinden AG, is involved in cytosolic Ca2C levels (P D 3.3 × 10−3) and AMPK stimulated fatty acid Kirichenko AV, Witteman JCM, oxidation in muscle (P D 4.1 × 10−3). Look-ups in bioinformatics resources showed Willemsen R, Oostra BA, Axenovich TI, van Duijn CM and that expression of FCRL2 is associated with ARHGAP24 and SETBP1 expression. Isaacs A (2016) A Combined Linkage This finding was not replicated in the Rotterdam study. Combining the bioinformatics and Exome Sequencing Analysis for Electrocardiogram Parameters information with the association and linkage analyses, FCRL2 emerges as a strong in the Erasmus Rucphen Family candidate gene for QT interval. Study. Front. Genet. 7:190. doi: 10.3389/fgene.2016.00190 Keywords: genetics, epidemiology, electrocardiography, linkage, exome Frontiers in Genetics | www.frontiersin.org 1 November 2016 | Volume 7 | Article 190 fgene-07-00190 November 4, 2016 Time: 17:11 # 2 Silva et al. Electrocardiogram Linkage Analysis INTRODUCTION region, where they were examined in person (Aulchenko et al., 2004). Interviews at the time of blood sampling were performed The electrocardiogram (ECG) is an important tool for by medical practitioners and included questions on a broad diagnosing, monitoring and evaluating risk in patients with range of topics, including current medication use and medical cardiovascular disease (CVD; Lin et al., 2013; Pelto et al., 2013). history (Sayed-Tabatabaei et al., 2005). Height and weight were ECG measurements, such as PR interval, QRS complex duration, measured with the participant in light underclothing and body and QT interval, are used for the diagnosis and prediction of mass index (kg/m2) was computed. Blood pressure (BP) was cardiac arrhythmias and sudden cardiac death (SCD; Kolder measured twice on the right arm in a sitting position after at et al., 2012). Myocardial depolarization and repolarization least five minutes rest, using an automated device (OMRON time are measured by the QT interval: the time between the 711, Omron Healthcare, Bannockburn, IL, USA). The average onset of the QRS complex and the end of the T wave. QT of the two measures was used for analysis. Hypertension was shortening or prolongation has been associated with an increased defined through the use of antihypertensive medication and/or risk for arrhythmias and SCD (Newton-Cheh and Shah, through the assessment of BP measurements according to the 2007). PR interval and QRS duration are measures of cardiac World Health Organization(1999) guidelines (individuals with conduction time; QRS duration reflects conduction through BP ≥ 140/90 mmHg should be regarded as hypertensive). The the ventricular myocardium, while PR interval measures atrial Medical Ethics Committee of the Erasmus University Medical and atrioventricular conduction from the sinoatrial node to the Center approved the ERF study protocol and all participants, or ventricular myocardium, primarily through the atrioventricular their legal representatives, provided written informed consent. node (Cheng et al., 2015; Mozos and Caraba, 2015). There are significant genetic contributions to ECG ECG Measurement and Interpretation measurements; genome-wide association studies (GWAS) Examinations included 10 s 12-lead ECG measurements, identified at least 71 common variants associated with their recorded with an ACTA-ECG (Esaote, Florence, Italy) with a variability (Arking et al., 2006, 2014; Newton-Cheh et al., 2007, sampling frequency of 500 Hz. Digital measurements of the ECG 2009; Pfeufer et al., 2009, 2010; Holm et al., 2010; Sotoodehnia parameters were made using the Modular ECG Analysis System et al., 2010). A number of these associations were established (MEANS; van Bemmel et al., 1990). Briefly, MEANS operates on in loci containing genes that encode proteins with previously multiple simultaneously recorded leads, which are transformed known roles in heart development and function, such as cardiac to a detection function that brings out the QRS complex and transcription factors; sodium, calcium, and potassium ion the other parts of the signal. MEANS determines common channels; genes with a role in myocardial electrophysiology; onsets and offsets for all 12 leads together on one representative and others involved in the conduction of electrical impulses averaged beat, with the use of template matching techniques. (Kolder et al., 2012). These include ARHGAP24, SETBP1, LRIG1, The measurement and diagnostic performance of MEANS have CREBBP, MEIS1, TBX20, and TBX5. Some ion channel encoding been extensively evaluated, both by the developers and by others genes, such as SCN5A, HERG, KCNE1, and KCNE2, have been (Willems et al., 1987, 1991; van Bemmel et al., 1990; de Bruyne associated with long QT syndrome (LQTS; Tristani-Firouzi et al., et al., 1997; Eijgelsheim et al., 2009). The MEANS criteria for MI 2001), atrial fibrillation (AF) and Brugada Syndrome (Hedley are mainly based on pathological Q waves, QR ratio, and R-wave et al., 2011). Collectively, however, these loci explain only modest progression (Leening et al., 2010). A cardiologist, specialized in proportions of phenotypic variability; GWAS SNPs specific for ECG methodology, ascertained the final diagnosis of MI. QT each trait account for limited trait heritability (17% for QRS, 4% interval was corrected for heart rate using Bazett’s formula in all for QT, and 2% for PR) (Silva et al., 2015). analyses (Funck-Brentano and Jaillon, 1993). Genome-wide association studies generally interrogate only common variants, typically of small effect. Families, in addition to being robust against population stratification, may be enriched Genotyping and Statistical Analyses of for less frequent variants, which can potentially be identified by the Linkage Study linkage and fine mapping. The aim of this study, therefore, was Illumina’s HumanHap6k Genotyping BeadChip (6K Illumina to discover less frequent variants using linkage analysis in a large Linkage IV Panels R ) was used for genotyping for the linkage family-based study, the Erasmus Rucphen Family Study (ERF).
Recommended publications
  • Targeted Sequence Capture and High-Throughput Sequencing in the Molecular Diagnosis of Ichthyosis and Other Skin Diseases

    Targeted Sequence Capture and High-Throughput Sequencing in the Molecular Diagnosis of Ichthyosis and Other Skin Diseases

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE providedCA by Elsevier Scott - Publisheret al. Connector Sequence Capture in Molecular Diagnosis of Skin Diseases Immunohistochemical staining indi- 1The Wellcome Trust Center for Human cause of Olmsted syndrome. Am J Hum cated that MBTPS2 is mainly expressed Genetics, Nuffield Department of Clinical Genet 90:558–64 Medicine, University of Oxford, Oxford, UK; Mevorah B, Goldberg I, Sprecher E et al. (2005) in the upper granular layer in normal 2 Centre for Cutaneous Research, The Blizard Olmsted syndrome: mutilating palmo- skin, as previously shown (Aten et al., Institute, Barts & The London School of plantar keratoderma with periorificial 2010); however, in OS skin, MBTPS2 Medicine and Dentistry, Queen Mary keratotic plaques. J Am Acad Dermatol 53: University of London, London, UK; S266–72 was expressed throughout the epi- 3 dermis (Figure 2c). There was no Department of Dermatology, Jundishapur Naiki M, Mizuno S, Yamada K et al. (2012) University of Medical Sciences, Ahvaz, Iran; MBTPS2 mutation causes BRESEK/BRESHECK 4 apparent difference in MBTPS2 locali- Genetic Department, Kerman University of syndrome. Am J Med Genet A 158A:97–102 zation in the skin of a KFSD patient with 5 Medical Sciences, Kerman, Iran and Darwin Oeffner F, Fischer G, Happle R et al. (2009) IFAP the p.N508S mutation (Aten et al., Building, University College London Genetics syndrome is caused by deficiency in MBTPS2, 2010). It is unclear why this is but it Institute, University College London, London, an intramembrane zinc metalloprotease essen- may be because of differences in UK tial for cholesterol homeostasis and ER stress E-mail: [email protected] response.
  • This Is an Author Produced Version of a Paper Published in Immunology

    This Is an Author Produced Version of a Paper Published in Immunology

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Publications from Karolinska Institutet This is an author produced version of a paper published in Immunology. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Pubmed citation for the paper: Immunology. 2014 May 6. [Epub ahead of print] Ligation of human Fc receptor like-2 (FCRL2) by monoclonal antibodies downregulates B cell receptor mediated signaling. Shabani M, Bayat AA, Jeddi-Tehrani M, Rabbani H, Hojjat-Farsangi M, Ulivieri C, Amirghofran Z, Baldari CT, Shokri F. URL: http://dx.doi.org/10.1111/imm.12311 Access to the published version may require subscription. Published with permission from: Wiley Ligation of human Fc receptor like-2 (FCRL2) by monoclonal antibodies downregulates B cell receptor mediated signaling Mahdi Shabania,b, Ali Ahmad Bayata, Mahmood Jeddi-Tehrania, Hodjatallah Rabbania,c, Mohammad Hojjat-Farsangid, Cristina Ulivierie, Zahra Amirghofranb, Cosima Tatiana Baldarie and Fazel Shokria,f* a Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran b Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran c Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden d Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Department of Oncology-Pathology, Karolinska Institutet, Stockholm e Department of Life Sciences, University of Siena, Siena, Italy f Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran *Corresponding author: Fazel Shokri, Ph.D., Professor, Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran, P.O.
  • Supplementary Table 1: Adhesion Genes Data Set

    Supplementary Table 1: Adhesion Genes Data Set

    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
  • ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center

    ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center

    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2008 ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Chemicals and Drugs Commons, and the Medical Sciences Commons Recommended Citation Fukuda, Yu , "ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters" (2008). Theses and Dissertations (ETD). Paper 345. http://dx.doi.org/10.21007/etd.cghs.2008.0100. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Interdisciplinary Program Research Advisor John D. Schuetz, Ph.D. Committee Linda Hendershot, Ph.D. James I. Morgan, Ph.D. Anjaparavanda P. Naren, Ph.D. Jie Zheng, Ph.D. DOI 10.21007/etd.cghs.2008.0100 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/345 ABCB6 IS A PORPHYRIN TRANSPORTER WITH A NOVEL TRAFFICKING SIGNAL THAT
  • ABCA12 (N-16): Sc-48435

    ABCA12 (N-16): Sc-48435

    SAN TA C RUZ BI OTEC HNOL OG Y, INC . ABCA12 (N-16): sc-48435 BACKGROUND CHROMOSOMAL LOCATION The ATP binding cassette (ABC) transporters, or traffic ATPases, constitute Genetic locus: ABCA12 (human) mapping to 2q35; Abca12 (mouse) mapping an expansive family of proteins accountable for the transport of a wide to 1 C3. variety of substrates across cell membranes in both prokaryotic and eukary - otic cells. They also aid in the regulation of lipid transport and membrane SOURCE trafficking. ABCA12 (ATP-binding cassette, subfamily A, member 12) contains ABCA12 (N-16) is an affinity purified goat polyclonal antibody raised against two transmembrane (TM) domains, each with six membrane-spanning seg - a peptide mapping within an internal region of ABCA12 of human origin. ments and two nucleotide-binding domains (NBDs), which are located in the cytoplasm. ABCA12 is expressed in normal human keratinocytes (RT-PCR PRODUCT reveals expression in placenta, testis, fetal brain and skin) and is upregulated during keratinization. Immunoelectron microscopy reveals that the ABCA12 Each vial contains 200 µg IgG in 1.0 ml of PBS with < 0.1% sodium azide protein is located in lamellar granules in the upper epidermal keratinocytes and 0.1% gelatin. of human skin. The ABCA12 gene, which synthesizes a 2,595 amino acid Blocking peptide available for competition studies, sc-48435 P, (100 µg protein, may produce an alternative splice variant with an in-frame deletion peptide in 0.5 ml PBS containing < 0.1% sodium azide and 0.2% BSA). leading to truncation of 79 amino acids. APPLICATIONS REFERENCES ABCA12 (N-16) is recommended for detection of ABCA12 of mouse, rat and 1.
  • Microsatellites As EWS/FLI Response Elements in Ewing's Sarcoma

    Microsatellites As EWS/FLI Response Elements in Ewing's Sarcoma

    Microsatellites as EWS/FLI response elements in Ewing’s sarcoma Kunal Gangwal*†, Savita Sankar*†, Peter C. Hollenhorst*†, Michelle Kinsey*†, Stephen C. Haroldsen†, Atul A. Shah†, Kenneth M. Boucher*†, W. Scott Watkins‡, Lynn B. Jorde‡, Barbara J. Graves*†, and Stephen L. Lessnick*†§¶ʈ *Department of Oncological Sciences, †Huntsman Cancer Institute, ‡Department of Human Genetics, §Huntsman Cancer Institute Center for Children, and ¶Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, UT 84112 Edited by Robert N. Eisenman, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved May 3, 2008 (received for review February 4, 2008) The ETS gene family is frequently involved in chromosome trans- in close proximity to low affinity binding sites for other tran- locations that cause human cancer, including prostate cancer, scription factors that allow for cooperative DNA binding. leukemia, and sarcoma. However, the mechanisms by which on- Ewing’s sarcoma was the first tumor in which ETS family cogenic ETS proteins, which are DNA-binding transcription factors, members were shown to be involved in chromosomal transloca- target genes necessary for tumorigenesis is not well understood. tions and serves as a paradigm for ETS-driven cancers (10). Ewing’s sarcoma serves as a paradigm for the entire class of Ewing’s sarcoma is a highly malignant solid tumor of children ETS-associated tumors because nearly all cases harbor recurrent and young adults that usually harbors a recurrent chromosomal chromosomal translocations involving ETS genes. The most com- translocation, t(11;22)(q24;q12), that encodes the EWS/FLI mon translocation in Ewing’s sarcoma encodes the EWS/FLI onco- fusion oncoprotein (10).
  • Transcriptional and Post-Transcriptional Regulation of ATP-Binding Cassette Transporter Expression

    Transcriptional and Post-Transcriptional Regulation of ATP-Binding Cassette Transporter Expression

    Transcriptional and Post-transcriptional Regulation of ATP-binding Cassette Transporter Expression by Aparna Chhibber DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmaceutical Sciences and Pbarmacogenomies in the Copyright 2014 by Aparna Chhibber ii Acknowledgements First and foremost, I would like to thank my advisor, Dr. Deanna Kroetz. More than just a research advisor, Deanna has clearly made it a priority to guide her students to become better scientists, and I am grateful for the countless hours she has spent editing papers, developing presentations, discussing research, and so much more. I would not have made it this far without her support and guidance. My thesis committee has provided valuable advice through the years. Dr. Nadav Ahituv in particular has been a source of support from my first year in the graduate program as my academic advisor, qualifying exam committee chair, and finally thesis committee member. Dr. Kathy Giacomini graciously stepped in as a member of my thesis committee in my 3rd year, and Dr. Steven Brenner provided valuable input as thesis committee member in my 2nd year. My labmates over the past five years have been incredible colleagues and friends. Dr. Svetlana Markova first welcomed me into the lab and taught me numerous laboratory techniques, and has always been willing to act as a sounding board. Michael Martin has been my partner-in-crime in the lab from the beginning, and has made my days in lab fly by. Dr. Yingmei Lui has made the lab run smoothly, and has always been willing to jump in to help me at a moment’s notice.
  • Supplementary Table 1 Genes Tested in Qrt-PCR in Nfpas

    Supplementary Table 1 Genes Tested in Qrt-PCR in Nfpas

    Supplementary Table 1 Genes tested in qRT-PCR in NFPAs Gene Bank accession Gene Description number ABI assay ID a disintegrin-like and metalloprotease with thrombospondin type 1 motif 7 ADAMTS7 NM_014272.3 Hs00276223_m1 Rho guanine nucleotide exchange factor (GEF) 3 ARHGEF3 NM_019555.1 Hs00219609_m1 BCL2-associated X protein BAX NM_004324 House design Bcl-2 binding component 3 BBC3 NM_014417.2 Hs00248075_m1 B-cell CLL/lymphoma 2 BCL2 NM_000633 House design Bone morphogenetic protein 7 BMP7 NM_001719.1 Hs00233476_m1 CCAAT/enhancer binding protein (C/EBP), alpha CEBPA NM_004364.2 Hs00269972_s1 coxsackie virus and adenovirus receptor CXADR NM_001338.3 Hs00154661_m1 Homo sapiens Dicer1, Dcr-1 homolog (Drosophila) (DICER1) DICER1 NM_177438.1 Hs00229023_m1 Homo sapiens dystonin DST NM_015548.2 Hs00156137_m1 fms-related tyrosine kinase 3 FLT3 NM_004119.1 Hs00174690_m1 glutamate receptor, ionotropic, N-methyl D-aspartate 1 GRIN1 NM_000832.4 Hs00609557_m1 high-mobility group box 1 HMGB1 NM_002128.3 Hs01923466_g1 heterogeneous nuclear ribonucleoprotein U HNRPU NM_004501.3 Hs00244919_m1 insulin-like growth factor binding protein 5 IGFBP5 NM_000599.2 Hs00181213_m1 latent transforming growth factor beta binding protein 4 LTBP4 NM_001042544.1 Hs00186025_m1 microtubule-associated protein 1 light chain 3 beta MAP1LC3B NM_022818.3 Hs00797944_s1 matrix metallopeptidase 17 MMP17 NM_016155.4 Hs01108847_m1 myosin VA MYO5A NM_000259.1 Hs00165309_m1 Homo sapiens nuclear factor (erythroid-derived 2)-like 1 NFE2L1 NM_003204.1 Hs00231457_m1 oxoglutarate (alpha-ketoglutarate)
  • L1 Antisense Promoter Drives Tissue-Specific Transcription Of

    L1 Antisense Promoter Drives Tissue-Specific Transcription Of

    Hindawi Publishing Corporation Journal of Biomedicine and Biotechnology Volume 2006, Article ID 71753, Pages 1–16 DOI 10.1155/JBB/2006/71753 Research Article L1 Antisense Promoter Drives Tissue-Specific Transcription of Human Genes Kert Matlik,¨ Kaja Redik, and Mart Speek Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 19086, Estonia Received 26 July 2005; Revised 11 November 2005; Accepted 16 November 2005 Transcription of transposable elements interspersed in the genome is controlled by complex interactions between their regulatory elements and host factors. However, the same regulatory elements may be occasionally used for the transcription of host genes. One such example is the human L1 retrotransposon, which contains an antisense promoter (ASP) driving transcription into adjacent genes yielding chimeric transcripts. We have characterized 49 chimeric mRNAs corresponding to sense and antisense strands of human genes. Here we show that L1 ASP is capable of functioning as an alternative promoter, giving rise to a chimeric transcript whose coding region is identical to the ORF of mRNA of the following genes: KIAA1797, CLCN5,andSLCO1A2. Furthermore, in these cases the activity of L1 ASP is tissue-specific and may expand the expression pattern of the respective gene. The activity of L1 ASP is tissue-specific also in cases where L1 ASP produces antisense RNAs complementary to COL11A1 and BOLL mRNAs. Simultaneous assessment of the activity of L1 ASPs in multiple loci revealed the presence of L1 ASP-derived transcripts in all human tissues examined. We also demonstrate that L1 ASP can act as a promoter in vivo and predict that it has a heterogeneous transcription initiation site.
  • ABCA12 Is the Major Harlequin Ichthyosis Gene Anna C

    ABCA12 Is the Major Harlequin Ichthyosis Gene Anna C

    ORIGINAL ARTICLE ABCA12 Is the Major Harlequin Ichthyosis Gene Anna C. Thomas1, Tom Cullup2, Elizabeth E. Norgett1, Tara Hill3, Stephanie Barton4, Beverly A. Dale5, Eli Sprecher6, Eamonn Sheridan7, Aileen E. Taylor8, Robert S. Wilroy9, Celia DeLozier10, Nigel Burrows11, Helen Goodyear12, Philip Fleckman5, Karen G. Stephens5, Lakshmi Mehta13, Rosemarie M. Watson14, Robert Graham15, Roni Wolf16, Anne Slavotinek17, Madelena Martin17, David Bourn4, Charles A. Mein2, Edel A. O’Toole1 and David P. Kelsell1 Harlequin ichthyosis (HI) is the most severe form of autosomal-recessive, congenital ichthyosis. Affected infants have markedly impaired barrier function and are more susceptible to infection. Abnormalities in the localization of epidermal lipids as well as abnormal lamellar granule formation are features of HI skin. Previously, we and others have shown that mutations in the ABCA12 gene encoding an adenosine triphosphate-binding cassette (ABC) transporter underlie the skin disease HI. In this study, we have sequenced the ABCA12 gene in an additional 14 patients and show that all contain mutations, with the majority being either nonsense substitution or frameshift mutations. Eleven HI patients had bi-allelic ABCA12 mutations, whereas in the remaining three HI patients in this study, ABCA12 mutations were detected on only one allele by sequencing. In addition, the one patient from the previous study where no sequence mutations were detected was screened for heterozygous deletions. A combination of oligonucleotide arrays, multiplex PCR analysis
  • Whole-Exome Sequencing Identifies Novel Mutations in ABC Transporter

    Whole-Exome Sequencing Identifies Novel Mutations in ABC Transporter

    Liu et al. BMC Pregnancy and Childbirth (2021) 21:110 https://doi.org/10.1186/s12884-021-03595-x RESEARCH ARTICLE Open Access Whole-exome sequencing identifies novel mutations in ABC transporter genes associated with intrahepatic cholestasis of pregnancy disease: a case-control study Xianxian Liu1,2†, Hua Lai1,3†, Siming Xin1,3, Zengming Li1, Xiaoming Zeng1,3, Liju Nie1,3, Zhengyi Liang1,3, Meiling Wu1,3, Jiusheng Zheng1,3* and Yang Zou1,2* Abstract Background: Intrahepatic cholestasis of pregnancy (ICP) can cause premature delivery and stillbirth. Previous studies have reported that mutations in ABC transporter genes strongly influence the transport of bile salts. However, to date, their effects are still largely elusive. Methods: A whole-exome sequencing (WES) approach was used to detect novel variants. Rare novel exonic variants (minor allele frequencies: MAF < 1%) were analyzed. Three web-available tools, namely, SIFT, Mutation Taster and FATHMM, were used to predict protein damage. Protein structure modeling and comparisons between reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively. Results: We detected a total of 2953 mutations in 44 ABC family transporter genes. When the MAF of loci was controlled in all databases at less than 0.01, 320 mutations were reserved for further analysis. Among these mutations, 42 were novel. We classified these loci into four groups (the damaging, probably damaging, possibly damaging, and neutral groups) according to the prediction results, of which 7 novel possible pathogenic mutations were identified that were located in known functional genes, including ABCB4 (Trp708Ter, Gly527Glu and Lys386Glu), ABCB11 (Gln1194Ter, Gln605Pro and Leu589Met) and ABCC2 (Ser1342Tyr), in the damaging group.
  • Computational Inferences of Mutations Driving Mesenchymal Differentiation in Glioblastoma

    Computational Inferences of Mutations Driving Mesenchymal Differentiation in Glioblastoma

    Computational Inferences of Mutations Driving Mesenchymal Differentiation in Glioblastoma James Chen Submitted in partial fulfillment of the requirements for the Doctor of Philosophy Degree in the Graduate School of Arts and Sciences Columbia University 2013 ! 2013 James Chen All rights reserved ABSTRACT Computational Inferences of Mutations Driving Mesenchymal Differentiation in Glioblastoma James Chen This dissertation reviews the development and implementation of integrative, systems biology methods designed to parse driver mutations from high- throughput array data derived from human patients. The analysis of vast amounts of genomic and genetic data in the context of complex human genetic diseases such as Glioblastoma is a daunting task. Mutations exist by the hundreds, if not thousands, and only an unknown handful will contribute to the disease in a significant way. The goal of this project was to develop novel computational methods to identify candidate mutations from these data that drive the molecular differentiation of glioblastoma into the mesenchymal subtype, the most aggressive, poorest-prognosis tumors associated with glioblastoma. TABLE OF CONTENTS CHAPTER 1… Introduction and Background 1 Glioblastoma and the Mesenchymal Subtype 3 Systems Biology and Master Regulators 9 Thesis Project: Genetics and Genomics 20 CHAPTER 2… TCGA Data Processing 23 CHAPTER 3… DIGGIn Part 1 – Selecting f-CNVs 33 Mutual Information 40 Application and Analysis 45 CHAPTER 4… DIGGIn Part 2 – Selecting drivers 52 CHAPTER 5… KLHL9 Manuscript 63 Methods 90 CHAPTER 5a… Revisions work-in-progress 105 CHAPTER 6… Discussion 109 APPENDICES… 132 APPEND01 – TCGA classifications 133 APPEND02 – GBM f-CNV list 136 APPEND03 – MES f-CNV candidate drivers 152 APPEND04 – Scripts 149 APPEND05 – Manuscript Figures and Legends 175 APPEND06 – Manuscript Supplemental Materials 185 i ACKNOWLEDGEMENTS I would like to thank the Califano Lab and my mentor, Andrea Califano, for their intellectual and motivational support during my stay in their lab.