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<I>BOC</I> Is a Modifier Gene in Holoprosencephaly
Received: 12 May 2017 Revised: 20 June 2017 Accepted: 28 June 2017 DOI: 10.1002/humu.23286 BRIEF REPORT BOC is a modifier gene in holoprosencephaly Mingi Hong1∗ Kshitij Srivastava2∗ Sungjin Kim1 Benjamin L. Allen3 Daniel J. Leahy4 Ping Hu2 Erich Roessler2 Robert S. Krauss1† Maximilian Muenke2† 1Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 2Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 3Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 4Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas Correspondence Robert S. Krauss (for editorial communication), Abstract Department of Cell, Developmental and Regen- Holoprosencephaly (HPE), a common developmental defect of the forebrain and midface, has a erative Biology, Icahn School of Medicine at complex etiology. Heterozygous, loss-of-function mutations in the sonic hedgehog (SHH) pathway Mount Sinai, New York, New York 10029. Email: [email protected] are associated with HPE. However, mutation carriers display highly variable clinical presentation, Maximilian Muenke, Medical Genetics Branch, leading to an “autosomal dominant with modifier” model, in which the penetrance and expressiv- National Human Genome Research Institute, ity of a predisposing mutation is graded by genetic or environmental modifiers. Such modifiers National Institutes of Health, Bethesda, Mary- land 20892. have not been identified. Boc encodes a SHH coreceptor and is a silent HPE modifier gene in mice. Email: [email protected] Here, we report the identification of missense BOC variants in HPE patients. Consistent with these ∗Mingi Hong and Kshitij Srivastava contributed alleles functioning as HPE modifiers, individual variant BOC proteins had either loss- or gain-of- equally to this work. -
Mutations in CDON, Encoding a Hedgehog Receptor, Result in Holoprosencephaly and Defective Interactions with Other Hedgehog Receptors
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ARTICLE Mutations in CDON, Encoding a Hedgehog Receptor, Result in Holoprosencephaly and Defective Interactions with Other Hedgehog Receptors Gyu-Un Bae,1,2,4,6 Sabina Domene´,3,4,7 Erich Roessler,3 Karen Schachter,1,8 Jong-Sun Kang,2,5,* Maximilian Muenke,3,5,* and Robert S. Krauss1,5 Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these structures. SHH signaling is regulated by a network of ligand-binding factors, including the primary receptor PTCH1 and the putative coreceptors, CDON (also called CDO), BOC, and GAS1. Although binding of SHH to these receptors promotes pathway activity, it is not known whether interactions between these receptors are important. We report here identification of missense CDON mutations in human HPE. These mutations diminish CDON’s ability to support SHH-dependent gene expression in cell-based signaling assays. The mutations occur outside the SHH-binding domain of CDON, and the encoded variant CDON proteins do not display defects in binding to SHH. In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. Our findings argue that CDON must associate with both ligand and other hedgehog-receptor components, particularly PTCH1, for signaling to occur and that disruption of the latter interactions is a mechanism of HPE. -
"The Genecards Suite: from Gene Data Mining to Disease Genome Sequence Analyses". In: Current Protocols in Bioinformat
The GeneCards Suite: From Gene Data UNIT 1.30 Mining to Disease Genome Sequence Analyses Gil Stelzer,1,5 Naomi Rosen,1,5 Inbar Plaschkes,1,2 Shahar Zimmerman,1 Michal Twik,1 Simon Fishilevich,1 Tsippi Iny Stein,1 Ron Nudel,1 Iris Lieder,2 Yaron Mazor,2 Sergey Kaplan,2 Dvir Dahary,2,4 David Warshawsky,3 Yaron Guan-Golan,3 Asher Kohn,3 Noa Rappaport,1 Marilyn Safran,1 and Doron Lancet1,6 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel 2LifeMap Sciences Ltd., Tel Aviv, Israel 3LifeMap Sciences Inc., Marshfield, Massachusetts 4Toldot Genetics Ltd., Hod Hasharon, Israel 5These authors contributed equally to the paper 6Corresponding author GeneCards, the human gene compendium, enables researchers to effectively navigate and inter-relate the wide universe of human genes, diseases, variants, proteins, cells, and biological pathways. Our recently launched Version 4 has a revamped infrastructure facilitating faster data updates, better-targeted data queries, and friendlier user experience. It also provides a stronger foundation for the GeneCards suite of companion databases and analysis tools. Improved data unification includes gene-disease links via MalaCards and merged biological pathways via PathCards, as well as drug information and proteome expression. VarElect, another suite member, is a phenotype prioritizer for next-generation sequencing, leveraging the GeneCards and MalaCards knowledgebase. It au- tomatically infers direct and indirect scored associations between hundreds or even thousands of variant-containing genes and disease phenotype terms. Var- Elect’s capabilities, either independently or within TGex, our comprehensive variant analysis pipeline, help prepare for the challenge of clinical projects that involve thousands of exome/genome NGS analyses. -
Duke University Dissertation Template
Gene-Environment Interactions in Cardiovascular Disease by Cavin Keith Ward-Caviness Graduate Program in Computational Biology and Bioinformatics Duke University Date:_______________________ Approved: ___________________________ Elizabeth R. Hauser, Supervisor ___________________________ William E. Kraus ___________________________ Sayan Mukherjee ___________________________ H. Frederik Nijhout Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Program in Computational Biology and Bioinformatics in the Graduate School of Duke University 2014 i v ABSTRACT Gene-Environment Interactions in Cardiovascular Disease by Cavin Keith Ward-Caviness Graduate Program in Computational Biology and Bioinformatics Duke University Date:_______________________ Approved: ___________________________ Elizabeth R. Hauser, Supervisor ___________________________ William E. Kraus ___________________________ Sayan Mukherjee ___________________________ H. Frederik Nijhout An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Program in Computational Biology and Bioinformatics in the Graduate School of Duke University 2014 Copyright by Cavin Keith Ward-Caviness 2014 Abstract In this manuscript I seek to demonstrate the importance of gene-environment interactions in cardiovascular disease. This manuscript contains five studies each of which contributes to our understanding of the joint impact of genetic variation -
Cdon Acts As a Hedgehog Decoy Receptor During Proximal-Distal Patterning of the Optic Vesicle
ARTICLE Received 10 Dec 2013 | Accepted 26 May 2014 | Published 8 Jul 2014 DOI: 10.1038/ncomms5272 OPEN Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle Marcos Julia´n Cardozo1,2, Luisa Sa´nchez-Arrones1,2,A´frica Sandonis1,2, Cristina Sa´nchez-Camacho2,w, Gaia Gestri3, Stephen W. Wilson3, Isabel Guerrero1 & Paola Bovolenta1,2 Patterning of the vertebrate optic vesicle into proximal/optic stalk and distal/neural retina involves midline-derived Hedgehog (Hh) signalling, which promotes stalk specification. In the absence of Hh signalling, the stalks are not specified, causing cyclopia. Recent studies showed that the cell adhesion molecule Cdon forms a heteromeric complex with the Hh receptor Patched 1 (Ptc1). This receptor complex binds Hh and enhances signalling activation, indicating that Cdon positively regulates the pathway. Here we show that in the developing zebrafish and chick optic vesicle, in which cdon and ptc1 are expressed with a complementary pattern, Cdon acts as a negative Hh signalling regulator. Cdon predominantly localizes to the basolateral side of neuroepithelial cells, promotes the enlargement of the neuroepithelial basal end-foot and traps Hh protein, thereby limiting its dispersion. This Ptc-independent function protects the retinal primordium from Hh activity, defines the stalk/retina boundary and thus the correct proximo-distal patterning of the eye. 1 Centro de Biologı´a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı´ficas—Universidad Auto´noma de Madrid, 28049 Madrid Spain. 2 Ciber de Enfermedades Raras (CIBERER), ISCIII, c/ Nicolas Cabrera 1, 28049 Madrid Spain. 3 Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. -
Hedgehog Pathway-Regulated Gene Networks in Cerebellum Development and Tumorigenesis
Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis Eunice Y. Leea, Hongkai Jib, Zhengqing Ouyangc, Baiyu Zhoud, Wenxiu Mae, Steven A. Vokesf, Andrew P. McMahong, Wing H. Wongd, and Matthew P. Scotta,1 aDepartments of Developmental Biology, Genetics, and Bioengineering, Howard Hughes Medical Institute, and Departments of cBiology, dStatistics and Health Research and Policy, and eComputer Science, Stanford University, Stanford, CA 94305; bDepartment of Biostatistics, Johns Hopkins University, Baltimore, MD, 21205; fSection of Molecular Cell and Development Biology, Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712; and gDepartment of Molecular and Cellular Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 Contributed by Matthew P. Scott, April 20, 2010 (sent for review November 24, 2009) Many genes initially identified for their roles in cell fate determi- genes influence murine MB development (18–21), so at least nation or signaling during development can have a significant part of the Shh-stimulated transcriptional program in GNPs is impact on tumorigenesis. In the developing cerebellum, Sonic active and functional during carcinogenesis. Genome-wide ex- hedgehog (Shh) stimulates the proliferation of granule neuron pression profiling has been widely used to understand the tran- precursor cells (GNPs) by activating the Gli transcription factors. scriptional effects of Shh signaling, but it does not distinguish Inappropriate activation of Shh target genes results in unrestrained direct and indirect effects. Many questions remain regarding the cell division and eventually medulloblastoma, the most common repertoire and regulation of Hh target genes and the extent of pediatric brain malignancy. We find dramatic differences in the their overlap in different tissues and cancers. -
Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss
cells Review Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss 1, 1, 1 1,2,3 1 Gayle B. Collin y, Navdeep Gogna y, Bo Chang , Nattaya Damkham , Jai Pinkney , Lillian F. Hyde 1, Lisa Stone 1 , Jürgen K. Naggert 1 , Patsy M. Nishina 1,* and Mark P. Krebs 1,* 1 The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; [email protected] (G.B.C.); [email protected] (N.G.); [email protected] (B.C.); [email protected] (N.D.); [email protected] (J.P.); [email protected] (L.F.H.); [email protected] (L.S.); [email protected] (J.K.N.) 2 Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand 3 Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand * Correspondence: [email protected] (P.M.N.); [email protected] (M.P.K.); Tel.: +1-207-2886-383 (P.M.N.); +1-207-2886-000 (M.P.K.) These authors contributed equally to this work. y Received: 29 February 2020; Accepted: 7 April 2020; Published: 10 April 2020 Abstract: Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. -
The Cell Surface Membrane Proteins Cdo and Boc Are Components and Targets of the Hedgehog Signaling Pathway and Feedback Network in Mice
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Cell 10, 647–656, May, 2006 ª2006 Elsevier Inc. DOI 10.1016/j.devcel.2006.04.004 The Cell Surface Membrane Proteins Cdo and Boc Are Components and Targets of the Hedgehog Signaling Pathway and Feedback Network in Mice Toyoaki Tenzen,1 Benjamin L. Allen,1 Francesca Cole,2 determining both the number and full range of ventral Jong-Sun Kang,2 Robert S. Krauss,2 cell types (reviewed in Ingham and McMahon, 2001). and Andrew P. McMahon1,* Patched-1 (Ptch1) encodes the vertebrate HH receptor 1 Department of Molecular and Cellular Biology while Hedgehog-interacting protein-1 (Hhip1) encodes Harvard University an unrelated membrane-associated protein that simi- 16 Divinity Avenue larly binds all mammalian HH ligands. Ptch1 and Hhip1 Cambridge, Massachusetts 02138 are upregulated in response to HH signaling; their feed- 2 Brookdale Department of Molecular, Cell, back functions serve to modify the range of signaling and Developmental Biology and regional response of target cells (Chuang and Box 1020 McMahon, 1999; Jeong and McMahon, 2005). A third Mount Sinai School of Medicine HH binding factor, Growth arrest-specific-1 (Gas1), is One Gustave L. Levy Place thought to inhibit Shh signaling; Gas1 is itself repressed New York, New York 10029 in response to HH signaling (Lee et al., 2001). Here we present evidence that Cdo and Boc, which encode cell surface bound members of the Ig/fibronectin domain Summary superfamily, are novel feedback components that act in a different manner, to enhance Shh signaling within Cdo and Boc encode cell surface Ig/fibronectin super- subregions of Shh’s neural target field. -
BOC Is a Modifier Gene in Holoprosencephaly
BOC is a Modifier Gene in Holoprosencephaly Mingi Hong1,5, Kshitij Srivastava2,5, Sungjin Kim1, Benjamin L. Allen3, Daniel J. Leahy4, Ping Hu2, Erich Roessler2, Robert S. Krauss1,6,7, and Maximilian Muenke2,6,7 1Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 10029. 2Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA 20892. 3Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA, 48109. 4Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA, 78712. 5 Contributed equally to this work 6 Contributed equally as senior authors 7Authors for correspondence: Robert S. Krauss (for editorial communication), Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Phone: 212-241-2177; Fax: 212-860-9279 e-mail: [email protected] This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/humu.23286. This article is protected by copyright. All rights reserved. Maximilian Muenke, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. e-mail: [email protected] Grant sponsors: This work was supported by grants NIH DE024748, GM118751, CA198074; Cancer Prevention and Research Institute of Texas (CPRIT) award RR160023; and by the Division of Intramural Research, NHGRI, NIH. -
Zebrafish Spinal Cord Oligodendrocyte Formation Requires Boc Function
bioRxiv preprint doi: https://doi.org/10.1101/2021.01.31.429029; this version posted January 31, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Kearns et al., 01/29/2021 1 Zebrafish spinal cord oligodendrocyte formation requires boc 2 function 3 4 Christina A. Kearns. Macie Walker, Andrew M. Ravanellia, Kayt Scott, Madeline R. Arzbeckerb and Bruce 5 Appel1 6 7 Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus and Children’s 8 Hospital Colorado, Aurora, Colorado, 80045, USA 9 10 a current address: MilliporeSigma, 2909 Laclede Ave., St. Louis, MO, USA 11 b current address: University of Wisconsin School of Medicine and Public Health, 750 Highland Ave. Madison, WI 53726 12 1 Correspondence: Bruce Appel, MS 8108, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045; 303- 13 724-3465; [email protected] 14 15 Abstract 16 The axis of the vertebrate neural tube is patterned, in part, by a ventral to dorsal gradient of Shh signaling. In the ventral spinal 17 cord, Shh induces concentration-dependent expression of transcription factors, subdividing neural progenitors into distinct domains 18 that subsequently produce distinct neuronal and glial subtypes. In particular, progenitors of the pMN domain express the bHLH 19 transcription factor Olig2 and produce motor neurons followed by oligodendrocytes, the myelinating glial cell type of the central 20 nervous system. -
Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein -
Pathway and Network Analysis for Mrna and Protein Profiling Data
Pathway and network analysis for mRNA and protein profiling data Bing Zhang, Ph.D. Professor of Molecular and Human Genetics Lester & Sue Smith Breast Center Baylor College of Medicine [email protected] VU workshop, 2016 Gene expression DNA Transcription Transcriptome Transcriptome RNA mRNA decay profiling Translation Proteome Protein Proteome Protein degradation profiling Phenotype Networks VU workshop, 2016 Overall workflow of gene expression studies Biological question Experimental design Microarray RNA-Seq Shotgun proteomics Image analysis Reads mapping Peptide/protein ID Signal intensities Read counts Spectral counts; Intensities Data Analysis Experimental Hypothesis validation VU workshop, 2016 Data matrix Samples probe_set_id HNE0_1 HNE0_2 HNE0_3 HNE60_1 HNE60_2 HNE60_3 1007_s_at 8.6888 8.5025 8.5471 8.5412 8.5624 8.3073 1053_at 9.1558 9.1835 9.4294 9.2111 9.1204 9.2494 117_at 7.0700 7.0034 6.9047 9.0414 8.6382 9.2663 121_at 9.7174 9.7440 9.6120 9.7581 9.7422 9.7345 1255_g_at 4.2801 4.4669 4.2360 4.3700 4.4573 4.2979 1294_at 6.3556 6.2381 6.2053 6.4290 6.5074 6.2771 Genes 1316_at 6.5759 6.5330 6.4709 6.6636 6.6438 6.4688 1320_at 6.5497 6.5388 6.5410 6.6605 6.5987 6.7236 1405_i_at 4.3260 4.4640 4.1438 4.3462 4.3876 4.6849 1431_at 5.2191 5.2070 5.2657 5.2823 5.2522 5.1808 1438_at 7.0155 6.9359 6.9241 7.0248 7.0142 7.0971 1487_at 8.6361 8.4879 8.4498 8.4470 8.5311 8.4225 1494_f_at 7.3296 7.3901 7.0886 7.2648 7.6058 7.2949 1552256_a_at 10.6245 10.5235 10.6522 10.4205 10.2344 10.3144 1552257_a_at 10.3224 10.1749 10.1992 10.2464 10.2191