DOCSLIB.ORG

Allelic Variation of the FRMD7 Gene in Congenital Idiopathic Nystagmus

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Allelic Variation of the FRMD7 Gene in Congenital Idiopathic Nystagmus OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD Allelic Variation of the FRMD7 Gene in Congenital Idiopathic Nystagmus James E. Self, BM, MRCOphth; Fatima Shawkat, PhD; Crispin T. Malpas, BM, MRCOphth; N. Simon Thomas, PhD; Christopher M. Harris, PhD; Peter R. Hodgkins, FRCOphth; Xiaoli Chen, BSc; Dorothy Trump, MD, FRCP; Andrew J. Lotery, MD, FRCOphth Objectives: To perform a genotype-phenotype corre- onstrated no clear causal link between skewing and vari- lation study in an X-linked congenital idiopathic nystag- able penetrance. mus pedigree (pedigree 1) and to assess the allelic vari- ance of the FRMD7 gene in congenital idiopathic Conclusions: We confirm profound phenotypic varia- nystagmus. tion in X-linked congenital idiopathic nystagmus pedi- grees. We demonstrate that other congenital nystagmus Methods: Subjects from pedigree 1 underwent de- genes exist besides FRMD7. We show that the role of X tailed clinical examination including nystagmology. inactivation in variable penetrance is unclear in congen- Screening of FRMD7 was undertaken in pedigree 1 and ital idiopathic nystagmus. in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence Clinical Relevance: We demonstrate that phenotypic changes. X-inactivation studies were performed in variation of nystagmus occurs in families with FRMD7 pedigree 1. mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystag- Results: The nystagmus phenotype was extremely vari- mus, the diagnostic yield is low. X-inactivation assays are able in pedigree 1. We identified 2 FRMD7 mutations. unhelpful as a test for carrier status for this disease. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies dem- Arch Ophthalmol. 2007;125(9):1255-1263 YSTAGMUS IS A DISORDER these pedigrees had causative FRMD7 mu- of oculomotor control tations. An additional 14 small pedigrees and can occur as an iso- with congenital idiopathic nystagmus and Author Affiliations: Clinical lated inherited trait, a an inheritance pattern consistent with X Neurosciences Division, congenital idiopathic linkage were screened and FRMD7 muta- University of Southampton Nnystagmus, or as secondary to other vi- tions were found in 8 of the pedigrees (Drs Self and Lotery and sual (sensory deficit nystagmus) or neu- (57%). Forty-two simplex cases were Ms Chen), and Southampton rological (neurological nystagmus) dis- screened for mutations in this gene and Eye Unit, Southampton General eases.1 In all cases, the underlying yielded 3 mutations (7%). Therefore, the Hospital (Drs Self, Shawkat, pathophysiology is poorly understood. overall contribution of FRMD7 mutations Malpas, Hodgkins, and Lotery), Furthermore, it is unclear which charac- to the cause of both X-linked and single- Southampton, England; Wessex Regional Genetics Laboratory, teristics of the nystagmus phenotype, if ton cases remains relatively unexplored. Salisbury District Hospital, any, are reliable as a diagnostic tool to help In X-linked congenital idiopathic nys- Salisbury, England identify underlying etiology. tagmus pedigrees, penetrance among fe- (Dr Thomas); SensoriMotor Congenital idiopathic nystagmus is ge- male obligate carriers has been vari- Laboratory, Centre for netically heterogeneous and has been de- able,3-5,7 ranging from 30% to 100%. Theoretical and Computational scribed as an autosomal dominant,2 auto- Possible mechanisms for this variability in- Neuroscience, University of somal recessive,3 X-linked dominant,3 or clude skewed X inactivation, genetic modi- Plymouth, Plymouth, England X-linked recessive4 trait. X-linked loci have fiers (such as polymorphisms within in- (Dr Harris); and Academic Unit been identified at Xp11.4-p11.34 and Xq26- teracting proteins), and other nongenetic of Medical Genetics, School of q27.3,5 In November 2006, Tarpey et al6 influences (such as environment) on ocu- Medicine and Centre for Molecular Medicine, Faculty of identified 22 nystagmus-causing muta- lomotor development. These factors may Medical and Human Sciences, tions in the FERM domain–containing 7 also explain why X-linked dominant and University of Manchester, (FRMD7) gene, which resides within the recessive pedigrees, with nystagmus or Manchester, England Xq26-q27 interval. Sixteen X-linked fami- other ocular diseases, can both show link- (Dr Trump). lies underwent linkage analysis and 15 of age to the same region.5,8,9 (REPRINTED) ARCH OPHTHALMOL / VOL 125 (NO. 9), SEP 2007 WWW.ARCHOPHTHALMOL.COM 1255 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 I:1 I:2 II:1 II:2 II:3 II:4 II:5 II:6 II:7 II:8 III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:8 III:9 III:10 III:11 III:12 III:13 III:14 III:15 III:16 III:17 III:18 III:19 III:20 IV:1 IV:2 IV:3 IV:4 IV:5 IV:6 IV:7 IV:8 IV:9 IV:10 IV:11 IV:12 IV:13 IV:14 IV:15 IV:16 IV:17 IV:18 IV:19 IV:20 IV:21 IV:22 IV:23 IV:24 IV:25 Underwent detailed phenotyping Unaffected male Affected male Unaffected female Affected female Obligate female carrier V:1 V:2 V:3 V:4 V:5 V:6 V:7 V:8 V:9 V:10 V:11 Figure 1. X-linked congenital idiopathic nystagmus pedigree (pedigree 1). This family has 9 affected males, 2 affected females, and 11 obligate female carriers. This article describes high-resolution phenotyping electrophysiological examination but without detailed eye move- using infrared limbal tracking, electrophysiology, and ment recordings. clinical examination in affected and unaffected mem- International Society for Clinical Electrophysiology of Vision– bers of a single large congenital nystagmus pedigree (pedi- standardized electroretinogram (http://www.iscev.org/) and vi- sual evoked potential tests were completed in 2 affected males gree 1) (Figure 1). The role of FRMD7 mutations in 9 and 2 obligate female carriers. Monocular stimulation and a other X-linked families and 28 simplex cases is investi- 3-channel transoccipital electrode montage were employed for gated and, in addition, studies of X inactivation are per- visual evoked potential recordings to optimize detection of neu- formed to investigate the hypothesis that skewing of X ronal misrouting suggestive of ocular albinism. Informed con- inactivation may be a major contributor to the variable sent was obtained from all subjects for genetic studies, and ge- penetrance seen in X-linked nystagmus pedigrees. nomic DNA was isolated from either blood or Oragene saliva sample kits (DNA Genotek Inc, Ottawa, Ontario, Canada). METHODS GENOTYPING AND The study had the approval of the local and regional ethics LINKAGE ANALYSIS committees and conformed to the tenets of the Declaration of Helsinki. Twenty-nine individuals (7 affected males, 2 af- We had previously shown by conventional linkage mapping techniques that the nystagmus gene in pedigree 1 links to an fected females, 11 obligate female carriers, and 9 unaffected 5 members) in a single congenital idiopathic nystagmus pedi- 8-cM region at Xq24-q26.3. This contains the FRMD7 gene, gree underwent detailed clinical examination (Figure 1), in- which is now known to be a cause of X-linked nystagmus and cluding tests for logarithm of the minimum angle of resolu- was thus investigated in this family. DNA was amplified using tion visual acuity, refraction, color vision, intraocular standard polymerase chain reaction (PCR) protocols. Primers pressure; anterior and posterior segment slitlamp examina- for FRMD7 (complementary DNA sequence NM_194277) were designed to include all 12 exons, splice sites, and both the 5Ј tion, including iris transillumination testing in a darkened Ј room; and orthoptic assessment. Twenty-four of these pa- and 3 untranslated regions in amplimers with fewer than 250 tients had detailed recordings of their nystagmus waveform base pairs (primers available on request). Pedigrees 2 through performed using Skalar IRIS IR Light Eye Tracker equipment 10 were not large enough to provide linkage information in- (Cambridge Research Systems Ltd, Rochester, England). dividually, and to avoid errors in light of known X-linked con- Twenty-four eye movement recordings were completed for genital idiopathic nystagmus locus heterogeneity, these fami- each patient. Binocular and uniocular saccades were recorded lies were not combined. Therefore, linkage information was not to calibrate amplitude measurements at ±10° and ±20° from ascertained for these families and definitive proof of X linkage fixation in the horizontal plain using a 1° red square target was not possible. moving at 500-millisecond intervals. Binocular and uniocular optokinetic nystagmus (OKN) measurements were carried SINGLE-STRAND CONFORMATIONAL out to rightward and leftward drifting gratings measuring 0.2 POLYMORPHISM ANALYSIS cycles per degree at a velocity of 25° per second. Waveforms were analyzed while viewed in 5 positions (primary, 10° right, Single-strand conformational polymorphism (SSCP) was per- 10° left, 20° right, and 20° left of fixation), both binocularly formed using standard techniques.10 Specifically, polyacryl- and uniocularly using a 1° red square target. amide gels with glycerol, 6%, were run for 3.5 hours at 25 W An additional 9 congenital idiopathic nystagmus pedigrees per gel at room temperature. We screened for sequence varia- with inheritance consistent with X linkage were identified tions in 96 female controls (182 control X chromosomes), fol- (Figure 2). These pedigrees had similarly detailed clinical and lowed by 2 affected subjects from the first pedigree, 9 pro- (REPRINTED) ARCH OPHTHALMOL / VOL 125 (NO. 9), SEP 2007 WWW.ARCHOPHTHALMOL.COM 1256 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Pedigree 2 Pedigree 3 Pedigree 4 Pedigree 5 Pedigree 6 Pedigree 7 Pedigree 8 Affected male Unaffected male Affected female Unaffected female Obligate female carrier Pedigree 9 Pedigree 10 Figure 2. Nine additional pedigrees screened for FRMD7 mutations. bands from other X-linked nystagmus pedigrees, and 28 cuts at the promoter site on the active (unmethylated) but not nystagmus simplex cases.
Load more

Recommended publications
  • 82262967.Pdf
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology 19, 1478–1484, September 15, 2009 ª2009 Elsevier Ltd All rights reserved DOI 10.1016/j.cub.2009.07.041 Report Key Features of the X Inactivation Process Are Conserved between Marsupials and Eutherians Shantha K. Mahadevaiah,1 Helene Royo,1 in situ hybridization (RNA FISH) [1] and semiquantitative John L. VandeBerg,2 John R. McCarrey,3 Sarah Mackay,4 reverse transcriptase-polymerase chain reaction (RT-PCR) and James M.A. Turner1,* [2] have concluded that the X chromosome of the marsupial 1MRC National Institute for Medical Research, Mill Hill, Monodelphis domestica (opossum) remains inactive during London NW7 1AA, UK spermiogenesis. However, Cot-1 RNA FISH has since been 2Department of Genetics, Southwest Foundation for shown to primarily detect silencing of repeat rather than Biomedical Research, San Antonio, TX 78227, USA coding X-linked sequences [16, 17], and RT-PCR cannot 3Department of Biology, University of Texas at San Antonio, discriminate between steady-state RNA levels and ongoing San Antonio, TX 78249, USA transcription. We therefore sought to reexamine male germline 4Division of Integrated Biology, Faculty of Biomedical & Life X silencing and its relationship to female XCI with a gene- Sciences, University of Glasgow, Glasgow G12 8QQ, specific RNA FISH approach. Scotland, UK For our analysis of XCI in the male germline, we selected ten genes distributed across the opossum X chromosome (Fig- ure 1A). We wished to compare X gene silencing in opossum Summary with that in mouse, in which MSCI and its maintenance have been well characterized [18, 19].
    [Show full text]
  • 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]
  • MBNL1 Regulates Essential Alternative RNA Splicing Patterns in MLL-Rearranged Leukemia
    ARTICLE https://doi.org/10.1038/s41467-020-15733-8 OPEN MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia Svetlana S. Itskovich1,9, Arun Gurunathan 2,9, Jason Clark 1, Matthew Burwinkel1, Mark Wunderlich3, Mikaela R. Berger4, Aishwarya Kulkarni5,6, Kashish Chetal6, Meenakshi Venkatasubramanian5,6, ✉ Nathan Salomonis 6,7, Ashish R. Kumar 1,7 & Lynn H. Lee 7,8 Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, 1234567890():,; targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A.Wefinally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins. 1 Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. 2 Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. 3 Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
    [Show full text]
  • Downloaded from [266]
    Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation by Allison Marie Cotton B.Sc., The University of Guelph, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2012 © Allison Marie Cotton, 2012 Abstract The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from X- chromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes.
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • Molecular Effects of Isoflavone Supplementation Human Intervention Studies and Quantitative Models for Risk Assessment
    Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis committee Promotors Prof. Dr Pieter van ‘t Veer Professor of Nutritional Epidemiology Wageningen University Prof. Dr Evert G. Schouten Emeritus Professor of Epidemiology and Prevention Wageningen University Co-promotors Dr Anouk Geelen Assistant professor, Division of Human Nutrition Wageningen University Dr Lydia A. Afman Assistant professor, Division of Human Nutrition Wageningen University Other members Prof. Dr Jaap Keijer, Wageningen University Dr Hubert P.J.M. Noteborn, Netherlands Food en Consumer Product Safety Authority Prof. Dr Yvonne T. van der Schouw, UMC Utrecht Dr Wendy L. Hall, King’s College London This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 20 June 2014 at 13.30 p.m. in the Aula. Vera van der Velpen Molecular effects of isoflavone supplementation: Human intervention studies and quantitative models for risk assessment 154 pages PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-952-0 ABSTRact Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology.
    [Show full text]
  • The Role of Cdep in the Embryonic Morphogenesis of Drosophila Melanogaster
    The Role of Cdep in the Embryonic Morphogenesis of Drosophila melanogaster Dissertation zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer.nat.) vorgelegt der Fakultät Mathematik und Naturwissenschaften der Technischen Universität Dresden von Anne Morbach Geboren am 05. August 1984 in Nordhausen, Deutschland Eingereicht am 30. Oktober 2015 Die Dissertation wurde in der Zeit von April 2012 bis Oktober 2015 im Max-Planck-Institut für molekulare Zellbiologie und Genetik angefertigt Gutachter: Prof. Dr. Elisabeth Knust Prof. Dr. Christian Dahmann Now, here, you see, it takes all the running you can do, to keep in the same place. Lewis Carroll, Through the Looking-Glass I Contents List of Figures V List of Tables VII Abstract IX List of Abbreviations XI 1 Introduction 1 1.1 Epithelial cell polarity . 1 1.1.1 Cellularization and formation of the primary epithelium . 1 1.1.1.1 Establishment of epithelial polarity and adhesion . 2 1.1.2 The epithelial polarity network . 3 1.1.3 Cell-cell adhesion . 5 1.1.3.1 Adherens junctions . 5 1.1.3.2 Septate junctions . 6 1.2 Epithelial movements in Drosophila embryonic morphogenesis . 6 1.2.1 Epithelial tube formation during Drosophila embryogenesis . 7 1.2.2 Coordinated migration of epithelial sheets during Dros. embryogenesis 7 1.2.2.1 FERM domain proteins in epithelial migration . 9 1.2.2.2 Cdep . 10 1.3 Mutagenesis with the CRISPR/Cas9 system . 12 2 Aim of My PhD Thesis Work 15 3 Preliminary Work 17 4 Results 19 4.1 A screen for novel regulators in Drosophila embryonic morphogenesis .
    [Show full text]
  • Structure-Based Screen Identification of a Mammalian Ste20-Like Kinase 4 (MST4) Inhibitor with Therapeutic Potential for Pituitary Tumors
    Published OnlineFirst December 31, 2015; DOI: 10.1158/1535-7163.MCT-15-0703 Small Molecule Therapeutics Molecular Cancer Therapeutics Structure-Based Screen Identification of a Mammalian Ste20-like Kinase 4 (MST4) Inhibitor with Therapeutic Potential for Pituitary Tumors Weipeng Xiong1,3, Christopher J. Matheson2, Mei Xu1,3, Donald S. Backos2, Taylor S. Mills1, Smita Salian-Mehta1, Katja Kiseljak-Vassiliades1,3, Philip Reigan2, and Margaret E. Wierman1,3 Abstract Pituitary tumors of the gonadotrope lineage are often large described as an Aurora kinase inhibitor, exhibited potent inhi- and invasive, resulting in hypopituitarism. No medical treat- bition of the MST4 kinase at nanomolar concentrations. The ments are currently available. Using a combined genetic and LbT2 gonadotrope pituitary cell hypoxic model was used to test genomic screen of individual human gonadotrope pituitary the ability of this inhibitor to antagonize MST4 actions. Under tumor samples, we recently identified the mammalian ster- short-term severe hypoxia (1% O2), MST4 protection from ile-20 like kinase 4 (MST4) as a protumorigenic effector, driving hypoxia-induced apoptosis was abrogated in the presence of increased pituitary cell proliferation and survival in response to hesperadin. Similarly, under chronic hypoxia (5%), hesperadin a hypoxic microenvironment. To identify novel inhibitors of blocked the proliferative and colony-forming actions of MST4 the MST4 kinase for potential future clinical use, computation- as well as the ability to activate specific downstream signaling al-based virtual library screening was used to dock the Sell- and hypoxia-inducible factor-1 effectors. Together, these data eckChem kinase inhibitor library into the ATP-binding site of identify hesperadin as the first potent, selective inhibitor of the the MST4 crystal structure.
    [Show full text]
  • X-Linked Diseases: Susceptible Females
    REVIEW ARTICLE X-linked diseases: susceptible females Barbara R. Migeon, MD 1 The role of X-inactivation is often ignored as a prime cause of sex data include reasons why women are often protected from the differences in disease. Yet, the way males and females express their deleterious variants carried on their X chromosome, and the factors X-linked genes has a major role in the dissimilar phenotypes that that render women susceptible in some instances. underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the Genetics in Medicine (2020) 22:1156–1174; https://doi.org/10.1038/s41436- heart, blood, skin, muscle, and bones. Summarized here are many 020-0779-4 examples of the different presentations in males and females. Other INTRODUCTION SEX DIFFERENCES ARE DUE TO X-INACTIVATION Sex differences in human disease are usually attributed to The sex differences in the effect of X-linked pathologic variants sex specific life experiences, and sex hormones that is due to our method of X chromosome dosage compensation, influence the function of susceptible genes throughout the called X-inactivation;9 humans and most placental mammals – genome.1 5 Such factors do account for some dissimilarities. compensate for the sex difference in number of X chromosomes However, a major cause of sex-determined expression of (that is, XX females versus XY males) by transcribing only one disease has to do with differences in how males and females of the two female X chromosomes. X-inactivation silences all X transcribe their gene-rich human X chromosomes, which is chromosomes but one; therefore, both males and females have a often underappreciated as a cause of sex differences in single active X.10,11 disease.6 Males are the usual ones affected by X-linked For 46 XY males, that X is the only one they have; it always pathogenic variants.6 Females are biologically superior; a comes from their mother, as fathers contribute their Y female usually has no disease, or much less severe disease chromosome.
    [Show full text]
  • Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis
    The Journal of Neuroscience, July 8, 2020 • 40(28):5413–5430 • 5413 Development/Plasticity/Repair Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis Victor Danelon,1* Ron Goldner,2* Edward Martinez,1 Irena Gokhman,2 Kimberly Wang,1 Avraham Yaron,2 and Tracy S. Tran1 1Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, and 2Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel Diverse neuronal populations with distinct cellular morphologies coordinate the complex function of the nervous system. Establishment of distinct neuronal morphologies critically depends on signaling pathways that control axonal and dendritic devel- opment. The Sema3A-Nrp1/PlxnA4 signaling pathway promotes cortical neuron basal dendrite arborization but also repels axons. However, the downstream signaling components underlying these disparate functions of Sema3A signaling are unclear. Using the KRK-AAA novel PlxnA4 knock-in male and female mice, generated by CRISPR/cas9, we show here that the KRK motif in the PlxnA4 cytoplasmic domain is required for Sema3A-mediated cortical neuron dendritic elaboration but is dispensable for inhibitory axon guidance. The RhoGEF FARP2, which binds to the KRK motif, shows identical functional specificity as the KRK motif in the PlxnA4 receptor. We find that Sema3A activates the small GTPase Rac1, and that Rac1 activity is required for dendrite elaboration but not axon growth cone collapse. This work identifies a novel Sema3A-Nrp1/PlxnA4/FARP2/Rac1 signaling pathway that specifi- cally controls dendritic morphogenesis but is dispensable for repulsive guidance events. Overall, our results demonstrate that the divergent signaling output from multifunctional receptor complexes critically depends on distinct signaling motifs, highlighting the modular nature of guidance cue receptors and its potential to regulate diverse cellular responses.
    [Show full text]
  • A Large-Scale Genome-Wide Association Study of Epistasis Effects of Production Traits and Daughter Pregnancy Rate in U.S
    G C A T T A C G G C A T genes Article A Large-Scale Genome-Wide Association Study of Epistasis Effects of Production Traits and Daughter Pregnancy Rate in U.S. Holstein Cattle Dzianis Prakapenka 1, Zuoxiang Liang 1, Jicai Jiang 2, Li Ma 3 and Yang Da 1,* 1 Department of Animal Science, University of Minnesota, Saint Paul, MN 55108, USA; [email protected] (D.P.); [email protected] (Z.L.) 2 Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA; [email protected] 3 Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA; [email protected] * Correspondence: [email protected] Abstract: Epistasis is widely considered important, but epistasis studies lag those of SNP effects. Genome-wide association study (GWAS) using 76,109 SNPs and 294,079 first-lactation Holstein cows was conducted for testing pairwise epistasis effects of five production traits and three fertility traits: milk yield (MY), fat yield (FY), protein yield (PY), fat percentage (FPC), protein percentage (PPC), and daughter pregnancy rate (DPR). Among the top 50,000 pairwise epistasis effects of each trait, the five production traits had large chromosome regions with intra-chromosome epistasis. The percentage of inter-chromosome epistasis effects was 1.9% for FPC, 1.6% for PPC, 10.6% for MY, 29.9% for FY, 39.3% for PY, and 84.2% for DPR. Of the 50,000 epistasis effects, the number of significant effects with log10(1/p) ≥ 12 was 50,000 for FPC and PPC, and 10,508, 4763, 4637 and 1 for MY, FY, PY and DPR, Citation: Prakapenka, D.; Liang, Z.; respectively, and A × A effects were the most frequent epistasis effects for all traits.
    [Show full text]
  • Splice Junction Identification from RNA-Sequencing Data Shaojun Tang1,2,3,4 and Alberto Riva1,2*
    Tang and Riva BMC Bioinformatics 2013, 14:116 http://www.biomedcentral.com/1471-2105/14/116 SOFTWARE Open Access PASTA: splice junction identification from RNA-Sequencing data Shaojun Tang1,2,3,4 and Alberto Riva1,2* Abstract Background: Next generation transcriptome sequencing (RNA-Seq) is emerging as a powerful experimental tool for the study of alternative splicing and its regulation, but requires ad-hoc analysis methods and tools. PASTA (Patterned Alignments for Splicing and Transcriptome Analysis) is a splice junction detection algorithm specifically designed for RNA-Seq data, relying on a highly accurate alignment strategy and on a combination of heuristic and statistical methods to identify exon-intron junctions with high accuracy. Results: Comparisons against TopHat and other splice junction prediction software on real and simulated datasets show that PASTA exhibits high specificity and sensitivity, especially at lower coverage levels. Moreover, PASTA is highly configurable and flexible, and can therefore be applied in a wide range of analysis scenarios: it is able to handle both single-end and paired-end reads, it does not rely on the presence of canonical splicing signals, and it uses organism-specific regression models to accurately identify junctions. Conclusions: PASTA is a highly efficient and sensitive tool to identify splicing junctions from RNA-Seq data. Compared to similar programs, it has the ability to identify a higher number of real splicing junctions, and provides highly annotated output files containing detailed information about their location and characteristics. Accurate junction data in turn facilitates the reconstruction of the splicing isoforms and the analysis of their expression levels, which will be performed by the remaining modules of the PASTA pipeline, still under development.
    [Show full text]