DOCSLIB.ORG

Generation of Novel Conditional and Hypomorphic Alleles of the Smad2 Gene and the Effects of Smad2 Removal in Environments with Elevated Retinoid Signaling

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Generation of Novel Conditional and Hypomorphic Alleles of the Smad2 Gene and the Effects of Smad2 Removal in Environments with Elevated Retinoid Signaling GENERATION OF NOVEL CONDITIONAL AND HYPOMORPHIC ALLELES OF THE SMAD2 GENE AND THE EFFECTS OF SMAD2 REMOVAL IN ENVIRONMENTS WITH ELEVATED RETINOID SIGNALING DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Maria Helen Festing, B.S. ***** The Ohio State University 2007 Dissertation Committee: Approved by Professor Michael Weinstein, Ph.D., Advisor Professor Susan Cole, Ph.D. _________________________________ Professor Harold Fisk, Ph.D. Advisor Graduate Program in Molecular Genetics Professor Amanda Simcox, Ph.D. ABSTRACT Smad2 is an intracellular mediator of the transforming growth factor beta (TGF-β) signaling pathway, and regulates target gene transcription. It has been previously shown that, in the mouse, removal of functional Smad2 results in embryonic lethality due to defects in gastrulation. To circumvent this early lethality, the Cre-loxP system was utilized to generate a Smad2 conditional allele. Cre-mediated recombination results in a deletion allele which phenocopies the previously reported Smad2ΔC null mutation. The hypomorphic allele Smad23loxP was also created that can be maintained as a homozygote. However, Smad23loxP/Δ embryos are lethal and encompass a variety of phenotypes, including craniofacial midline defects. Holoprosencephaly (HPE) comprises a spectrum of craniofacial midline defects and is a congenital cephalic disorder. Many candidate factors have been identified that are associated with HPE in humans and animals, which include excessive alcohol and retinoic acid exposure, and mutations or deletions at 12 genetic loci. Seven of these 12 loci have been identified, and include TGIF. TGIF is a corepressor of the retinoid signaling pathway, and removal of this ii repressor results in increased retinoid signaling. TGIF can also function in as a corepressor the transforming growth factor-beta (TGF-β) pathway, interacting with Smad2. Research has indicated that mouse embryos harboring Tgif mutations are more susceptible to teratogenesis induced by exogenous all-trans retinoic acid (atRA) when compared to wild-type littermates, and frequently display HPE. Interestingly, embryos harboring either Smad2 null or hypomorphic alleles are also more susceptible to atRA teratogenesis, and frequently display HPE. Embryos that harbor mutations in both Smad2 and Tgif exhibit a partially- penetrant craniofacial phenotype, which encompasses the HPE spectrum. This indicates that retinoid signaling may be involved in these HPE phenotypes. There are many proteins involved in retinoid signaling, which includes both the retinoid signaling cascade and retinol metabolism. Analysis of gene transcription to determine a possible inherent susceptibility to teratogenesis in Smad2 heterozygous embryos indicated that Adh4 and Cyp26A1, which are both involved in retinol metabolism, were reduced in early embryonic stages when forebrain development is beginning. These transcriptional reductions do not by themselves result in lethality, but when combined with any other factor that perturbs retinoid signaling, HPE can result. Finally, as another method to affect retinoid signaling, a Cyp26A1 null allele was bred to the Smad2 heterozygotes. Consistent with affecting retinoid signaling, the Cyp26A1-/-; Smad2ΔE9,10/+ embryos display midline defects, including HPE. iii DEDICATION To my mother Fran, my father Tom, my brother Tommy, and my grandparents Bill and Helen, for their support and patience over the years. It is necessary to learn when to follow, and when to lead. iv ACKNOWLEDGMENTS I wish to thank my advisor, Dr. Michael Weinstein, for his advice and for allowing me to pursue the project designs, and Dr. Susan Cole, for helping with lab supplies. I am grateful to all my committee members throughout my graduate education: Dr. Susan Cole, Dr. Harold Fisk, Dr. Michael Ostrowski, and Dr. Amanda Simcox for their encouragement. I thank current and former members of the Weinstein Laboratory including Dr. Tessa Carrel, Dr. Mark Hester, Dr. Ye Liu, Samuel Lasse, Kara Keplinger, Samantha McCarthy, J Chris Thompson, Andy Chow, and Joe Mills for their insight, help, and discussion over the years. I also wish to thank Dr. Heithem El- Hodiri for his expertise in helping to perform the Xenopus laevis micro-injections. Finally, I wish to thank the editors of Genesis for the use of the previously published text and figures that are used in this dissertation. Generation of Novel Conditional and Hypomorphic Alleles of the Smad2 Gene, 40:118-123, is reprinted with the permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. v VITA 30 March 1979………………… Born – Tacoma, WA. May 2000………………………. The Pennsylvania State University, State College, PA. Biology (Genetics), BS. 2002 – present………………… Graduate Teaching Assistant. The Ohio State University. PUBLICATIONS Ye Liu, Maria Festing, John C Thompson, Mark Hester, Scott Rankin, Heithem M El-Hodiri, Aaron M Zorn, and Michael Weinstein. Smad2 and Smad3 coordinately regulate craniofacial and endodermal development. Dev Biol. 2004 June 15; 270(2): 411-426. Ye Liu, Maria H Festing, Mark Hester, John C Thompson, and Michael Weinstein. Generation of novel conditional and hypomorphic alleles of the Smad2 gene. Genesis. 2004 Oct; 40(2):118-123. FIELD OF STUDY Major Field: Molecular Genetics vi TABLE OF CONTENTS Page Abstract ……………………………………………………………………………….. ii Dedication…………………………………………………………………………….. iv Acknowledgments…………………………………………………………………… v Vita…………………………………………………………………………………….. vi List of Tables…………………………………………………………………………. x List of Figures……………………………………………………………………….. xi List of Abbreviations………………………………………………………………… xiii Chapters: 1. Introduction……………………………………………………………………. 1 1.1 Introduction……………………………………………………………. 1 1.2 Development of the Early Mouse Embryo…………………………. 2 1.3 Neural Tube Development and Defects……………………………. 3 1.3.1 Neural Tube Formation and Neural Tube Defects.………. 3 1.3.2 Prosencephalic Development an Holoprosencephaly...… 4 1.4 TGF-β Superfamily Signaling…………...………………………...… 6 1.4.1 The Receptors…….……………………………………….…. 7 1.4.2 The Smads………….……………………………………....... 8 2. Generation of Smad2 Conditional and Hypomorphic Alleles…………….. 16 2.1 Introduction……………………………………………………………. 16 2.2 Results……………………………………………………………….... 17 2.2.1 Creation and Confirmation of the Smad2 Alleles…………. 17 2.2.2 Smad2 3loxP Allele is Hypomorphic……………………….. 21 2.2.3 Conditional Removal of Smad2…………………………….. 24 2.3 Conclusions………………………………………………….………... 26 vii 2.4 Materials…………….………………………………………………… 28 2.4.1 Generation of Targeted ES Cells and Creation of Germline Chimeric Mice….…………………………………. 28 2.4.2 Southern Blot………………………………………………..... 29 2.4.3 Mice and Matings…………………………………………….. 30 2.4.4 Genotyping……………………………………………………. 31 2.4.5 Histology………………………………………………………. 32 2.4.6 Hematoxylin and Eosin Staining…………………………… 33 2.4.7 Xenopus laevis Injection Assay…………………………….. 34 2.4.8 RNA Extraction……………………………………………….. 35 2.4.9 Real-Time PCR…………………………………………...….. 36 3. Removal of Smad2 Results in Increased Sensitivity to Retinoic Acid Induced Holoprosencephaly…………………………………………………. 50 3.1 Introduction…………….……………………………………………… 50 3.1.1 Retinoic Acid Metabolism…………………………………… 51 3.1.2 Retinoid Signaling……………………………………………. 52 3.1.3 Retinoid Signaling Affects TGF-β Signaling………………. 54 3.2 Results………………………………………………………………… 55 3.2.1 Retinoic Acid Signaling is Affected in Smad2 Embryos…. 55 3.2.2 Sensitivity of Smad2 Embryos to Retinoic Acid Teratogenesis………………………………………………… 57 3.2.3 Retinoic Acid Metabolizing Enzymes ADH4 and Cyp26A1 are Affected in Smad2 Embryos……….…………...……… 59 3.3 Conclusions………………………………………………………….. 62 3.4 Materials…………….………………………………………………… 64 3.4.1 Mice and Matings…………………………………………….. 64 3.4.2 Genotyping……………………………………………………. 64 3.4.3 Teratogenic Application of Retinoic Acid………………….. 65 3.4.4 Whole Mount Visualization of β-galactosidase Expression……………………………………………………. 65 3.4.5 Quantification of β-galactosidase expression…………….. 66 3.4.6 RNA Extraction and Analysis……………………………….. 67 3.4.7 Real-Time PCR………………………...…………………….. 68 4. Smad2 and Tgif, in Addition to Strain Background, Work in Concert to Cause Murine Holoprosencephaly 80 4.1 Introduction….………………………………………………………… 80 4.2 Results………………………………………………………………… 80 4.2.1 Expression Domain of Tgif and Tgif2………………………. 80 4.2.2 Retinoid Signaling Affected in Tgif Embryos…………….... 83 4.2.3 Frequency and Penetrance of Holoprosencephaly in 84 Smad2/Tgif Embryos………………………………………… 4.2.4 Molecular Analysis of Smad2/Tgif Embryos………………. 87 4.2.5 Sensitivity of Smad2/Tgif Embryos to Retinoic Acid……... 89 4.3 Conclusions…………………...………………………………………. 90 4.4 Materials……………….……………………………………………… 94 viii 4.4.1 Mice and Matings…………………………………………….. 94 4.4.2 Genotyping……………………………………………….…… 95 4.4.3 Histology……………………………………………….……… 95 4.4.4 Whole Mount In Situ Hybridization………………….……… 96 4.4.5 Teratogenic Application of Retinoic Acid………….………. 99 4.4.6 RNA Extraction and Analysis……………………….………. 100 5. Smad2 and Cyp26A1 Mutations Work in Concert to Cause Murine Holoprosencephaly..…………..……………………………………………… 113 5.1 Introduction……………………………………………………………. 113 5.2 Results……………………………………………………...……….… 115 5.2.1 Frequency and Penetrance of Holoprosencephaly in 115 Smad2/Cyp26A1 Embryos….………………………………. 5.2.2 Cyp26A1 and the Smad2 Hypomorphic Allele…………… 117 5.2.3 Smad2, Cyp26A1, and Tgif………………….…………….... 117 5.3 Conclusions…………………………………………………………… 119 5.4 Materials...…………………………………………………………….. 120 5.4.1 Mice and
Load more

Recommended publications
  • (12) Patent Application Publication (10) Pub. No.: US 2007/0254315 A1 Cox Et Al
    US 20070254315A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0254315 A1 Cox et al. (43) Pub. Date: Nov. 1, 2007 (54) SCREENING FOR NEUROTOXIC AMINO (60) Provisional application No. 60/494.686, filed on Aug. ACID ASSOCATED WITH NEUROLOGICAL 12, 2003. DSORDERS Publication Classification (75) Inventors: Paul A. Cox, Provo, UT (US); Sandra A. Banack, Fullerton, CA (US); Susan (51) Int. Cl. J. Murch, Cambridge (CA) GOIN 33/566 (2006.01) GOIN 33/567 (2006.01) Correspondence Address: (52) U.S. Cl. ............................................................ 435/721 PILLSBURY WINTHROP SHAW PITTMAN LLP (57) ABSTRACT ATTENTION: DOCKETING DEPARTMENT Methods for screening for neurological disorders are dis P.O BOX 105OO closed. Specifically, methods are disclosed for screening for McLean, VA 22102 (US) neurological disorders in a Subject by analyzing a tissue sample obtained from the subject for the presence of (73) Assignee: THE INSTITUTE FOR ETHNO elevated levels of neurotoxic amino acids or neurotoxic MEDICINE, Provo, UT derivatives thereof associated with neurological disorders. In particular, methods are disclosed for diagnosing a neu (21) Appl. No.: 11/760,668 rological disorder in a subject, or predicting the likelihood of developing a neurological disorder in a Subject, by deter (22) Filed: Jun. 8, 2007 mining the levels of B-N-methylamino-L-alanine (BMAA) Related U.S. Application Data in a tissue sample obtained from the subject. Methods for screening for environmental factors associated with neuro (63) Continuation of application No. 10/731,411, filed on logical disorders are disclosed. Methods for inhibiting, treat Dec. 8, 2003, now Pat. No. 7,256,002.
    [Show full text]
  • Holoprosencephaly and Strabismus
    Holoprosencephaly and Strabismus Pavlina Kemp, MD, Grant Casey, Susannah Longmuir, MD June 11, 2012 Chief complaint Eye crossing History of Present Illness The patient is a 15 month-old female at presentation to the eye clinic, with history of severe hydrocephalus at birth. She was also diagnosed with alobar holoprosencephaly at birth with seizures. She was originally referred for eye crossing. We present her remarkable clinical course. Past Medical History: • Hydrocephalus s/p ventriculoperitoneal shunting • Holoprosencephaly (alobar type) • Seizure disorder Past Surgical History: • Ventriculoperitoneal shunt placement, 2004 • Ventriculoperitoneal shunt revision, 1/2005 • Ventriculoperitoneal shunt revision, 6/2005 Family History: No known family history of holoprosencephaly, amblyopia or strabismus. Social History: Patient lives at home with parents and two sisters. Medications: None Exam and Clinical Course: Age: 15 months Visual Acuity: Central, unsteady and maintained OD and central, unsteady and maintained OS Teller acuity testing: • Without correction OU: 20/800 Pupils: Equally round and briskly reactive, no relative afferent pupillary defect. Stereo Vision: Unable to test Motility and Strabismus: • Large variable esotropia • Bilateral elevation and abduction deficits • Intermittent horizontal nystagmus Cycloplegic Refraction: • OD: +4.00 • OS: +6.00 External Exam: Notable for large head circumference Slit Lamp Exam: Normal anterior segment exam OU without evidence of cataracts or other media opacities. Normal appearing optic nerves and normal dilated fundus examination. No sign of optic nerve hypoplasia in either eye. Figure 1: Axial and saggital MRI illustrating the enlargement of ventricles secondary to hydrocephalus. At this point, after discussion with her family, surgery for strabismus was deferred and correction of her hyperopia was attempted.
    [Show full text]
  • PDF Download
    Review Xatzipsalti Maria et al. Congenital Hypopituitarism: Various Genes, … Horm Metab Res 2018; 00: 00–00 Congenital Hypopituitarism: Various Genes, Various Phenotypes Authors Maria Xatzipsalti1, 2, Antonis Voutetakis1, Lela Stamoyannou2, George P. Chrousos1, Christina Kanaka-Gantenbein1 Affiliations ABSTRacT 1 Division of Endocrinology, Diabetes and Metabolism, The ontogenesis and development of the pituitary gland is a First Department of Pediatrics, Medical School, National highly complex process that depends on a cascade of transcrip- and Kapodistrian University of Athens, “Aghia Sofia” tion factors and signaling molecules. Spontaneous mutations Children's Hospital, Athens, Greece and transgenic murine models have demonstrated a role for 2 First Department of Pediatrics, “Aglaia Kyriakou” many of these factors, including HESX1, PROP1, PIT1, LHX3, Children's Hospital, Athens, Greece LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, SHH, GLI2, and FGF8 in the etiology of congenital hypopituitarism. Genetic muta- Key words tions in any of these factors can lead to congenital hypopitui- pituitary, combined pituitary hormone deficiency, congenital tarism, which is characterized by the deficiency in one or more hypopituitarism, transcription factors, syndromic hypopitui- pituitary hormones. The phenotype can be highly variable, tarism, non-syndromic hypopituitarism consisting of isolated hypopituitarism or more complex disor- ders. The same phenotype can be attributed to different gene received 27.03.2018 mutations; while a given gene mutation can
    [Show full text]
  • Engineering Region-Specific Brain Organoids from Human Stem Cells to Study Neural Development and Disease
    CHAPTER TWELVE Building the brain from scratch: Engineering region-specific brain organoids from human stem cells to study neural development and disease Fadi Jacoba,b,c, Jordan G. Schnolla, Hongjun Songa,d,e,f, and Guo-li Minga,d,e,g,* aDepartment of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States bThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States cMedical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, United States dDepartment of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States eInstitute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, United States fThe Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States gDepartment of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States *Corresponding author: e-mail address: [email protected] Contents 1. Introduction 478 1.1 Fundamentals of mammalian brain development 479 1.2 Human-specific features 482 1.3 Comparison of in vitro human cell models 482 2. Generation of region-specific brain organoids from human stem cells 484 2.1 Unguided differentiation: Cerebral organoids 484 2.2 Guided differentiation: Region-specific brain organoids 489 3. Advancements in cellular complexity of brain organoids 496 3.1 Fusion of region-specific brain organoids 497 3.2 Enhancing glial cell production and maturation 499 3.3 Reconstitution of resident immune cells and vasculature 500 3.4 Technical modifications for long-term culture 501 3.5 In vivo orthotopic xenotransplantation 503 4.
    [Show full text]
  • Prenatal Diagnosis of Congenital Fetal Malformations Medically Terminated: a Retrospective Analysis
    DOI - 10.21276/obgyn.2021.8.1.13 ISSN Print – 2454-2334; ISSN Online – 2454-2342 RESEARCH ARTICLE Prenatal diagnosis of congenital fetal malformations medically terminated: a retrospective analysis Papa Dasari, Pratima Aggrawal Corresponding author: Dr. Papa Dasari, Professor, Department of Obstetrics and Gynaecology, JIPMER, Puducherry, India; Email: [email protected] Distributed under Attribution-Non Commercial – Share Alike 4.0 International (CC BY-NC-SA 4.0) ABSTRACT Objectives: The primary objective of this study is to find out demographic and clinical profile of women with congenital malformation who underwent MTP and secondary objective is to find out types of congenital malformations, risk factors and method of termination of pregnancy. Methods: This retrospective cohort involved women with congenital malformations who underwent medical termination (MTP) over a 3 year period (July 2016 to June 2019) in a tertiary care facility. Data was analysed with respect to gestational age and spectrum of malformations and results were expressed as frequencies and proportions. Results: Of the 640 women underwent MTP, 245 were for congenital fetal malformations (38.2%). The mean age was 25 years, 95% belonged to low socioeconomic status and from rural background and were Hindus. The most common system affected was CNS (55.5%) followed by renal. The most common lethal anomalies were anencepahaly and hydrocephalous. Majority were diagnosed between 16 to 20 weeks and only 3 % were diagnosed in first trimester. Risk factors were third and second degree consanguinity (27%), diabetes in pregnancy (28%) and non consumption of folic acid preconceptionally (92%). Conclusion: The most common anomalies are largely preventable as they involved CNS and 40% were anencephaly.
    [Show full text]
  • Colpocephaly in Newborn: Case Report and Literature Review
    Submitted on: 05/14/2017 Approved on: 09/05/2017 CASE REPORT Colpocephaly in newborn: case report and literature review Rafael Pimentel Saldanha1, José Alfredo Lacerda de Jesus2, Bruna Mathias Silva1, Wesley Flávio de Lima Junior3 Keywords: Abstract infant, newborn, Colpocephaly is a rare cephalic disorder caused by an abnormal development of the central nervous system. It is neonatology, characterized by a disproportionate enlargement of the occipital horns of the lateral ventricles and other potential brain lateral ventricles, malformations. Here we report the case of a preterm neonate who underwent cranial ultrasonography examinations brain, that showed bilateral periventricular hyperechogenicity and colpocephaly. The information about the described case was agenesis of corpus obtained through medical record review, photographic documentation of the tests performed on the newborn, and a callosum. review of the current literature. This case report and the collected references seek to clarify the features of colpocephaly and provide an adequate understanding of its diagnostic, therapeutic, and prognostic aspects. 1 MD Pediatric resident. Hospital Universitario de Brasilia. Universidade de Brasilia. Brasilia, DF. Brazil. 2 MD, PhD. Adjunct Professor on Childhood and Adolescent Medicine. Universidade de Brasilia. Brasilia, DF. Brazil. 3 Medical student. Universidade de Brasilia. Brasilia, DF. Brazil. Correspondence to: Rafael Pimentel Saldanha. Universidade de Brasília (UnB). SQN 211, Bloco H, Apto 211. Asa Norte. Brasília - DF. Brazil. Zip Code: 70863-080. E-mail: [email protected] Residência Pediátrica 2017;7(3):110-113. DOI: 10.25060/residpediatr-2017.v7n3-06 110 INTRODUCTION showed bilateral periventricular hyperechogenicity and left- side colpocephaly. Later, on the 43rd postnatal day (or the Colpocephaly is a rare anatomic finding of the brain.
    [Show full text]
  • A Case of Iniencephaly in a 36 Week-Old Human Female Fetus
    ORIGINAL ARTICLE Eur. J. Anat. 17 (4): 209-219 (2013) A case of iniencephaly in a 36 week-old human female fetus Ernest F. Talarico, Jr.,1 and Theodore M. Hiemstra2 1Anatomy & Cell Biology, Indiana University School of Medicine-Northwest, Gary, Indiana, USA 2Department of Biological Sciences, Purdue University Calumet, Hammond, Indiana, USA SUMMARY ment of a NTD and useful information for clini- The purpose of this investigation was to charac- cians to distinguish iniencephaly from similar de- terize iniencephaly, a neural tube defect (NTD), fects. in a 36-38 week-old human female fetus. Inien- cephaly is a fatal, anatomic anomaly that lacks Key words: Human fetus – Iniencephaly – a direct etiology. However, multiple factors (i.e., Esophageal atresia – Renal atresia – Spina bifida medications, teratogens, nutrient deficiency, etc.) suggest a shared causation. Clinically, it is im- portant to differentiate iniencephaly from other NTDs and conditions that can be treated such Abbreviations: anterior (A); bronchi (B); carina as nuchal tumor, Klippel-Feil syndrome (KFS) (C); computed tomography (CT); esophagus (E); and Sprengel’s deformity, etc. The fetus was foot or inferior (F); left (L); magnetic resonance evaluated by physical examination, gross meas- imaging (MRI); methylenetetrahydrofolate re- urement, observation and dissection. To examine ductase (MTHFR); coronal (COR); axial (AX); the defects associated with iniencephaly, digital sagittal (SAG); multi-planar reformatting (MPR); radiologic image acquisition was done using full neural tube defect (NTD); posterior (P); right (R); -body x-ray films, and high-resolution CT Scans three-dimensional (3D); trachea (T); weighted and MRI Scans. Image analysis, multi-planar (Wtd); Klippel-Feil Syndrome (KFS); intrauterine reformatting, and 3D-reconstruction were done growth retardation (IUGR) on radiographic series.
    [Show full text]
  • December Issue 4, P
    VOLUME 45 NUMBER 4 DECEMBER 2013 KMJ KUWAIT MEDICAL JOURNAL The Official Journal of The Kuwait Medical Association EDITORIAL Diabetes, Antidiabetic Drugs, and Cancer: Separating Background Risk from Iatrogenesis 283 Intekhab Ahmed, Samuel Dagogo-Jack REVIEW ARTICLE Metabolic Acidosis in the Critically Ill and Continuous Renal Replacement Therapy – A Review 286 Prashant G Kedlaya ORIGINAL ARTICLES Association between Patients’ Sociodemographic Characteristics and Their Satisfaction with Primary Health Care Services in Turkey 291 Davut Baltaci, Recep Eroz, Handan Ankarali, Ozgur Erdem, Ahmet Celer, Yasemin Korkut Antenatal Ultrasound Diagnosis of Fetal Anomalies at a University Hospital 300 Naglaa Mostafa Elsayed, Sondos Abuzenadah Electrophysiologic Effects of Statins in Patients with Ischemic Cardiomyopathy and Ventricular Tachyarrhythmia 307 Aleks Degirmencioglu, Gultekin Karakus, Ali Buturak, Nazmiye Cakmak, Ilke Sipahi, Ahmet Akyol Variant Analysis of the Sirtuin (SIRT1) Gene in Multiple Sclerosis 313 Tuba Gokdogan Edgunlu, Sevim Karakas Celik, Ufuk Emre, Aysun Eroglu Unal, Ahmet Dursun Acquired Multiple Clotting Factor Inhibitors in Children 319 Adekunle Adekile, Asmaa Farag Azab, Rajaa Marouf, Sundus Al-Sharida, Hanan Al-Abboh Predictors of Quality of Life in Renal Transplant Recipients 324 Rizna Abdul Cader, Rozita Mohd, Halim Abdul Gafor, Rafidah Mamat, Norhayati Arrifin CASE REPORTS Extraperitoneal Presentation of Pseudomyxoma Peritonei as a Pleural Effusion: A Case Report 329 Mohamad Abdulrahman Tayeb, Ersan Al-Zamel Colobronchial
    [Show full text]
  • Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions
    molecules Review Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions April L. Darling 1,2,* ID and Vladimir N. Uversky 1,3,* ID 1 Department of Molecular Medicine, College of Medicine, Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL 33612, USA 2 James A. Haley Veteran’s Hospital, Tampa, FL 33612, USA 3 Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia * Correspondence: [email protected] (A.L.D.); [email protected] (V.N.U.); Tel.: +1-813-396-9249 (A.L.D.); +1-813-974-5816 (V.N.U.) Received: 8 November 2017; Accepted: 21 November 2017; Published: 24 November 2017 Abstract: Intrinsically disordered proteins and proteins with intrinsically disordered regions have been shown to be highly prevalent in disease. Furthermore, disease-causing expansions of the regions containing tandem amino acid repeats often push repetitive proteins towards formation of irreversible aggregates. In fact, in disease-relevant proteins, the increased repeat length often positively correlates with the increased aggregation efficiency and the increased disease severity and penetrance, being negatively correlated with the age of disease onset. The major categories of repeat extensions involved in disease include poly-glutamine and poly-alanine homorepeats, which are often times located in the intrinsically disordered regions, as well as repeats in non-coding regions of genes typically encoding proteins with ordered structures. Repeats in such non-coding regions of genes can be expressed at the mRNA level. Although they can affect the expression levels of encoded proteins, they are not translated as parts of an affected protein and have no effect on its structure.
    [Show full text]
  • A Review on Craniofacial Anomalies Bhaskaran Sathyapriya1, Chandrakala B 2, Misbahsubhani G3, Angel V.C3govindarajan Sumathy*
    European Journal of Molecular & Clinical Medicine ISSN 2515-8260 Volume 07, Issue 10, 2020 A Review on Craniofacial Anomalies Bhaskaran Sathyapriya1, Chandrakala B 2, MisbahSubhani G3, Angel V.C3Govindarajan Sumathy* 1. Professor, Department of Anatomy, Sree Balaji Dental College & Hospital, Bharath Institute of Higher Education & Research, Chennai. 2. Senior Lecturer, Department of Anatomy, Sree Balaji Dental College & Hospital, Bharath Institute of Higher Education & Research, Chennai. 3. Graduate student, Sree Balaji Dental College and Hospital, Bharath Institute of Higher Education and Research * Professor and Head, Department of Anatomy, Sree Balaji Dental College & Hospital, Bharath Institute of Higher Education & Research, Chennai. Abstract: Craniofacial anomalies (CFA) are a diverse group of deformities in the growth of the head and facial bones. Anomaly is a medical term meaning "irregularity" or "different from normal." These abnormalities are present at birth (congenital) and there are numerous variations. Some craniofacial anomalies are associated with anomalies elsewhere in the body, which can be serious. Cranio facial malformations include a variety of anomalies, including cleft lip with or without cleft palate, craniosynostosis, hemangioma, vascular malformation, and hemifacialmicrosomia. Congenital craniofacial abnormalities frequently require ophthalmic evaluation and surgical management. The term craniofacial anomalies include all congenital deformities of cranium and face. More specifically it refers to the deformities of the head that interfere with physical and mental well-being of an individual. It mainly deals with the understanding when, where and how the genes are expressed with specific pattern of morphogenesis. Keywords: Craniofacial anomalies, Cleft lip, Cleft palate, Craniosynostosis, Hemangioma, Vascular malformation. Introduction: A craniofacial malformation is an anomaly of embryonic development that results in a serious impairment of the normal anatomy of skull, jaws and adjacent soft tissues.
    [Show full text]
  • Neonatal Agenesis of Corpus Callosum in a Pregnant Lady with Multiple Endocrine Neoplasia Type I
    Journal of Gynecology and Women’s Health ISSN 2474-7602 Case Report J Gynecol Women’s Health Volume 12 Issue 1 - September 2018 Copyright © All rights are reserved by Dabbour S DOI: 10.19080/JGWH.2018.12.555827 Neonatal Agenesis of Corpus Callosum in a Pregnant Lady with Multiple Endocrine Neoplasia Type I Dabbour S1*, Aref A2 and Rengert E1 1Princess Alexandra Hospital, United Kingdom 2The Fetal Medicine Unit, University College Hospital London, UK Submission: August 27, 2018; Published: September 19, 2018 *Corresponding author: Sheriff Dabbour, Princess Alexandra Hospital, Hamstel Rd, Harlow CM20 1QX; UK, Email: Abstract baby with agenesis of the corpus callosum (ACC), colpocephaly and some dysmorphic facial features. (MEN Type I) is a rare inherited disorder causedThis by is tumor the first of the reported neuroendocrinal case of a pregnant tissue and woman may be diagnosed associated with with Multiple some clinical Endocrine symptoms. Neoplasia The type main 1 aim (MEN of managementType I) who deliveredis to assess a hemispheres.and manage potential Agenesis complications of corpus callosum that might (ACC) happen may beto theassociated mother withand her early baby seizures, [1,2]. The eye corpus abnormalities, callosum hydrocephalus, (CC) is the flat bundle developmental of white delaymatter and commissural other abnormalities. fibers beneath Colpocephaly the cerebral is a cortexcephalic spanning disorder part involving of the thelongitudinal disproportionate fissure and enlargement connecting of the the left occipital and right horns cerebral of the lateral ventricles and is usually diagnosed by cranial ultrasonography early after birth. We report a case of a 35-year-old multigravida with fetala confirmed growth restriction.diagnosis of The MEN neonate Type wasI prior born to inconception.
    [Show full text]
  • Vol4 No.2.Pdf
    CASE REPORT Iniencephaly Apertus - A Rare Neural Tube Defect Abstract Iniencephaly is a rare congenital malformation of the CNS, affecting the nape of the neck, occipital bone and cervical vertebrae. Sometimes it is associated with encephalocoele and in such cases it is called as iniencephaly apertus. Gaddam Vijaya We are reporting a case of iniencephaly apertus seen in our institution. It is caused by Lakshmi defective closure of the neural tube at multiple sites. Closure of neural tube requires adequate formation of paraxial mesoderm in the early Anju George embryonic stage. Primary paraxial mesodermal insufficiency results in different types of neural tube defects. Rincy Thomas Key words: Iniencephaly apertus, Neural tube defect, Multisite closure of neural tube, Paraxial mesodermal insufficiency. Introduction one, and then referred to our hospital. On Iniencephaly is a rare congenital admission, she was in labour and underwent malformation of the CNS, occurring prior to abortion. The expelled products of conception closure of cephalic neural fold. The defect were studied in detail. lies in the mid-cervical and occipital regions1. On examination, the conceptus was of male It was first described by Saint Hilare in 1836. sex and was small for age. It presented gross Lewis, in 1897 classified it into iniencephaly dysmorphic features with a disproportionately clausus (no encephalocoele) and large head, which was retroflexed on the iniencephaly apertus (encephalocoele is cervical spine (Fig. 1). Neck was absent. The present)2. skin of the face was connected directly to The malformation affects three regions, anterior chest wall. Similarly, the posterior namely, the nape of the neck (inion means scalp was directly connected to skin of the nape of the neck), the occipital bone and the back of the thoracic region.
    [Show full text]