Abstract

Oculocutaneous syndromes are often due to mutations in single genes. In some cases, mouse models for these diseases exist in spontaneously occurring mutations, or in mice resulting from forward mutatagenesis screens. Here we present novel genes that may be causative for oculocutaneous disease in humans, discovered as part of a genome-wide screen of knockout-mice in a targeted single-gene deletion project. The International Mouse Phenotyping Consortium (IMPC) database (data release 10.0) was interrogated for all mouse strains with integument abnormalities, which were then cross-referenced individually to identify knockouts with concomitant ocular abnormalities attributed to the same targeted gene deletion. The search yielded 307 knockout strains from unique genes with integument abnormalities, 226 of which have not been previously associated with oculocutaneous conditions. Of the 307 knockout strains with integument abnormalities, 52 were determined to have ocular changes attributed to the targeted deletion, 35 of which represent novel oculocutaneous genes. Some examples of various integument abnormalities are shown, as well as two examples of knockout strains with oculocutaneous phenotypes. Each of the novel genes provided here are potentially relevant to the pathophysiology of human integumentary, or oculocutaneous conditions, such as albinism, phakomatoses, or other multi-system syndromes. The novel genes reported here may implicate molecular pathways relevant to these human diseases and may contribute to the discovery of novel therapeutic targets.

Details

Title
Genome-wide screening of mouse knockouts reveals novel genes required for normal integumentary and oculocutaneous structure and function
Author
Moore, Bret A 1 ; Flenniken, Ann M 2 ; Clary, Dave 3 ; Moshiri, Ata S 4   VIAFID ORCID Logo  ; Nutter, Lauryl M J 5 ; Berberovic, Zorana 2 ; Owen, Celeste 2 ; Newbigging, Susan 5 ; Adissu, Hibret 5 ; Eskandarian, Mohammad 2 ; McKerlie, Colin 6   VIAFID ORCID Logo  ; Brown, Steve 7 ; Wells, Sara 7 ; Mallon, Ann-Marie 7 ; Beaudet, Arthur L 8 ; Martin Hrabe de Angelis 9 ; Karp, Natasha 10 ; Braun, Bob 11 ; Herault, Yann 12 ; Gao, Xiang 13 ; Obata, Yuichi 14 ; Flicek, Paul 15 ; Meehan, Terrence 15 ; Parkinson, Helen 15 ; Smedley, Damian 16 ; Seong, J K 17 ; Tocchini-Valentini, Glauco 18 ; Mammano, Fabio 18 ; Thomasy, Sara M 19 ; Lloyd, K C Kent 3   VIAFID ORCID Logo  ; Murphy, Christopher J 19 ; Moshiri, Ala 20 

1  William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California Davis, Davis, CA, United States 
2  The Centre for Phenogenomics, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada 
3  Department of Surgery, School of Medicine, and Mouse Biology Program, University of California Davis, Davis, CA, United States 
4  Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, United States 
5  The Centre for Phenogenomics, Toronto, ON, Canada; The Hospital for Sick Children, Toronto, ON, Canada 
6  The Centre for Phenogenomics, Toronto, ON, Canada 
7  Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, UK 
8  Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 
9  German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany 
10  The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK 
11  The Jackson Laboratory, Bar Harbor, ME, USA 
12  Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France; Centre National de la Recherche Scientifique, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, Illkirch, France; Université de Strasbourg, Illkirch, France; CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), CNRS, INSERM, University of Strasbourg, Illkirch, Graffenstaden, France 
13  SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China 
14  RIKEN BioResource Center, Tsukuba, Ibaraki, Japan 
15  European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK 
16  Clinical Pharmacology, Charterhouse Square, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 
17  Korea Mouse Phenotyping Consortium (KMPC) and BK21 Program for Veterinary Science, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Gwanak-gu, Seoul, South Korea 
18  Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Adriano Buzzati-Traverso Campus, Via Ramarini, Monterotondo Scalo, Italy 
19  Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States; Department of Ophthalmology & Vision Science, School of Medicine, University of California Davis, Sacramento, CA, United States 
20  Department of Ophthalmology & Vision Science, School of Medicine, University of California Davis, Sacramento, CA, United States 
Pages
1-9
Publication year
2019
Publication date
Aug 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-47286-2
ProQuest document ID
2267715547
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.