MEDIA RELEASE FOR IMMEDIATE RELEASE 10 JANUARY 2017 HOW DOES A NOSE FORM? SCIENTISTS IN SINGAPORE DISCOVER THE NOSE GENE Different mutations in this gene are also linked to a common type of muscular dystrophy. Singapore — Scientists in Singapore have identified the gene which allows the nose to form when the baby develops in the mother’s womb. When this gene, SMCHD1, is mutated, the nose does not form, resulting in a condition known as congenital arhinia. This discovery brings new insights on how the nose is formed during the development of the embryo (embryogenesis) and sheds new light on how variation in nose shape and size can evolve between individuals and among animal species. This SMCHD1 gene has also previously been linked with a more common muscular disease known as facioscapulohumeral muscular dystrophy type 2 (FSHD2). This adult onset muscle- weakening disorder affects the face (facio), shoulders (scapula) and upper arms (humeral), and can spread to other parts of the body over time. A better understanding of SMCHD1 will provide valuable insights for the development of novel therapy for this disorder. About arhinia Children born with arhinia, or the absence of a nose, have breathing and feeding difficulties and in some cases, eye abnormalities. Picture credit: A*STAR Institute of Medical Biology. A rare genetic condition, arhinia was first reported in 1981 and its genetic basis has remained elusive till now. Fewer than 100 cases have been reported in medical literature to date. The absence of a nose has a significant impact on a child’s early life, as babies naturally breathe through their noses when breastfeeding. This condition requires them to undergo a Pg. 1 tracheotomy to circumvent the absence of nasal airways. Babies born without a nose may also have eye defects. Children without a nose will never experience the sense of smell, a condition known as anosmia. Some individuals also have reproductive defects which first manifest as delayed puberty, or hypogonadotropic hypogonadism. Discovering the mutation of the nose gene The team found that a single gene, SMCHD1, was mutated in all 14 of the unrelated cases that were studied. SMCHD1 is an epigenetic regulator, an important factor that switches on or off important genes depending on the cellular context. Prior to this study, the gene has never been associated with craniofacial development in humans but has previously been associated with causing a completely unrelated muscular disorder, FSHD)type 2. Professor Bruno Reversade, Research Director at Institute of Medical Biology (IMB) and Institute of Molecular and Cell Biology (IMCB) and co-corresponding author said, “This discovery is a fascinating example of how rare conditions can provide unsuspected insights into common diseases. We will strive to translate these findings into potential therapeutics for FSHD. ” Professor Birgitte Lane, Executive Director of IMB, said, “This unexpected and totally new finding has come from an excellent example of cross-institutional and international collaboration. The combined strength of several genetic and medical experts has led to a great piece of world-class scientific research. We all benefit from these very creative partnerships and we look forward to more of them in the future.” Professor Hong Wanjin, Executive Director of IMCB, said, “This finding is a critical inroad to understanding the development and evolution of the nose, and will shed new insight for many others in the scientific and clinical community.” The discovery, published in Nature Genetics on 9 January 2017, was led by researchers from A*STAR’s Institute of Medical Biology, Institute of Molecular and Cell Biology and Genome Institute of Singapore in collaboration with a multinational team of researchers and clinicians from Institut Imagine (Paris, France), University Medical Center Göttingen (Göttingen, Germany) and The Walter and Eliza Hall Institute of Medical Research (Melbourne, Australia). ANNEX A - About the Reversade Lab Note for Editors: The research findings described in this media release can be found in the 9th January 2017 online issue of Nature Genetics, under the title “De novo mutations in SMCHD1 abrogate nasal development” by Christopher T. Gordon1,2*, Shifeng Xue3,4*, Gökhan Yigit5*, Hicham Filali1,2,6*, Kelan Chen7,8*, Nadine Rosin5, Koh-ichiro Yoshiura9, Myriam Oufadem1,2, Tamara J. Beck7, Ruth McGowan10, Alex C. Magee11, Janine Altmüller12,13, Camille Dion14, Holger Pg. 2 Thiele12, Alexandra D. Gurzau7,8, Peter Nürnberg12,15,16, Dieter Meschede17, Wolfgang Mühlbauer18, Nobuhiko Okamoto19, Vinod Varghese20, Rachel Irving20, Sabine Sigaudy21, Denise Williams22, S. Faisal Ahmed23, Carine Bonnard3, Mung Kei Kong3, Ilham Ratbi6, Nawfal Fejjal24, Meriem Fikri25, Siham Chafai Elalaoui6,26, Hallvard Reigstad27, Christine Bole-Feysot2,28, Patrick Nitschké2,29, Nicolas Lévy14,21, Gökhan Tunçbilek30, Audrey S.M. Teo31, Michael L. Cunningham32, Abdelaziz Sefiani6,26, Hülya Kayserili33, James M. Murphy7,8, Chalermpong Chatdokmaiprai34, Frédérique Magdinier14, Axel M. Hillmer31, Duangrurdee Wattanasirichaigoon35, Stanislas Lyonnet1,2,36, Asif Javed31#, Marnie E. Blewitt7,8#, Jeanne Amiel1,2,36#, Bernd Wollnik5,13#, Bruno Reversade3,4,33,37,38# 1Laboratory of embryology and genetics of congenital malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France. 2Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France. 3Human Genetics and Embryology Laboratory, Institute of Medical Biology, A*STAR, Singapore. 4Institute of Molecular and Cell Biology, A*STAR, Singapore. 5Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany. 6Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Mohammed V University, Rabat, Morocco. 7The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. 8The University of Melbourne, Melbourne, Australia. 9Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4, Sakamoto, Nagasaki, Japan. 10West of Scotland Regional Genetics Service, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow, UK. 11Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK. 12Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany. 13Institute of Human Genetics, University of Cologne, Cologne, Germany. 14Aix Marseille Université, INSERM, Génétique Médicale et Génomique Fonctionnelle (GMGF), UMR S_910, Marseille, France. 15Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. 16Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. 17Praxis für Humangenetik, Cologne, Germany. 18Plastische und Ästhetische Chirurgie, ATOS Klinik München, Munich, Germany. 19Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan. 20Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK. 21Département de Génétique Médicale, Hôpital Timone Enfant, Assistance Publique - Hôpitaux de Marseille, Marseille, France. 22West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, UK. 23Developmental Endocrinology Research Group, University of Glasgow, RHC, Glasgow, UK. Pg. 3 24Service de chirurgie plastique pédiatrique, Hôpital d'Enfants, CHU Ibn Sina, Mohammed V University, Rabat, Morocco. 25Service de neuroradiologie, Hôp 57 ital des Spécialités, CHU Ibn Sina, Mohammed V University, Rabat, Morocco. 26Département de Génétique Médical, Institut National d'Hygiène, Rabat, Morocco. 27Neonatal Intensive Care Unit, Children’s Department, Haukeland University Hospital, Bergen, Norway. 28Genomic Platform, INSERM UMR 1163, Institut Imagine, Paris, France. 29Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, Paris, France. 30Hacettepe University Faculty of Medicine, Department of Plastic, Reconstructive and Aesthetic Surgery, Ankara, Turkey. 31Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR, Singapore. 32University of Washington Department of Pediatrics, Division of Craniofacial Medicine and Seattle Children’s Hospital Craniofacial Center, Seattle, USA. 33Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey. 34Plastic and Maxillofacial Surgery, Department of Surgery, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 35Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 36Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique 77 - Hôpitaux de Paris, Paris, France. 37Department of Paediatrics, School of Medicine, National University of Singapore, Singapore. 38Amsterdam Reproduction & Development, Academic Medical Centre & VU University Medical Center, Amsterdam, the Netherlands. *co-first authors #co-last authors Correspondence should be addressed to: J.A. ([email protected]), B.W ([email protected]) and B.R. ([email protected]). For media queries and clarifications, please contact: Ms Sunanthar Lu Senior Officer, Corporate Communications Agency for Science, Technology and Research Tel: +65 6517 1966 Email: [email protected] Pg. 4 About A*STAR’s Institute of Medical Biology (IMB) IMB is one of the youngest Biomedical