Journal article
SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome
Nature genetics, Vol.49(2), pp.238-248
02/2017
DOI: 10.1038/ng.3743
PMCID: PMC5473428
PMID: 28067909
Abstract
Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.
Details
- Title: Subtitle
- SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome
- Creators
- Natalie D Shaw - National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USAHarrison Brand - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USAZachary A Kupchinsky - Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USAHemant Bengani - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKLacey Plummer - Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USATakako I Jones - Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USASerkan Erdin - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USAKathleen A Williamson - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKJoe Rainger - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKAlexei Stortchevoi - Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USAKaitlin Samocha - Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USABenjamin B Currall - Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USADonncha S Dunican - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKRyan L Collins - Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USAJason R Willer - Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USAAngela Lek - Department of Genetics, Harvard Medical School, Boston, Massachusetts, USAMonkol Lek - Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USAMalik Nassan - Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USAShahrin Pereira - Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USATammy Kammin - Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USADiane Lucente - Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USAAlexandra Silva - Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USACatarina M Seabra - GABBA Program, University of Porto, Porto, PortugalColby Chiang - Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USAYu An - Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USAMorad Ansari - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKJacqueline K Rainger - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKShelagh Joss - West of Scotland Genetics Service, South Glasgow University Hospitals, Glasgow, UKJill Clayton Smith - Faculty of Medical and Human Sciences, Institute of Human Development, Manchester Centre for Genomic Medicine, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UKMargaret F Lippincott - Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USASylvia S Singh - Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USANirav Patel - Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USAJenny W Jing - Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USAJennifer R Law - Division of Pediatric Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USANalton Ferraro - Department of Oral and Maxillofacial Surgery, Boston Children's Hospital, Boston, Massachusetts, USAAlain Verloes - Department of Genetics, Robert Debré Hospital, Paris, FranceAnita Rauch - Institute of Medical Genetics and Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, SwitzerlandKatharina Steindl - Institute of Medical Genetics and Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, SwitzerlandMarkus Zweier - Institute of Medical Genetics and Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, SwitzerlandIanina Scheer - Department of Diagnostic Imaging, Children's Hospital, Zurich, SwitzerlandDaisuke Sato - Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, JapanNobuhiko Okamoto - Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, JapanChristina Jacobsen - Division of Endocrinology and Genetics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USAJeanie Tryggestad - Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USASteven Chernausek - Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USALisa A Schimmenti - Departments of Otorhinolaryngology and Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USABenjamin Brasseur - DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USAClaudia Cesaretti - Medical Genetics Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, ItalyJose E García-Ortiz - División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, MexicoTatiana Pineda Buitrago - Fundación Hospital Infantil Universitario de San José, Bogotá, ColombiaOrlando Perez Silva - Academia Nacional de Medicina de Colombia, Bogotá, ColombiaJodi D Hoffman - Divisions of Genetics and Maternal Fetal Medicine, Tufts Medical Center, Boston, Massachusetts, USAWolfgang Mühlbauer - Department of Plastic and Aesthetic Surgery, ATOS Klinik, Munich, GermanyKlaus W Ruprecht - Department of Ophthalmology, University Hospital of the Saarland, Homburg, GermanyBart L Loeys - Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, BelgiumMasato Shino - Department of Otolaryngology and Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, JapanAngela M Kaindl - Biology and Neurobiology, Charité-University Medicine Berlin and Berlin Institute of Health, Berlin, GermanyChie-Hee Cho - Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, University Hospital of Bern, Bern, SwitzerlandCynthia C Morton - Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USARichard R Meehan - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKVeronica van Heyningen - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKEric C Liao - Harvard Stem Cell Institute, Cambridge, Massachusetts, USARavikumar Balasubramanian - Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USAJanet E Hall - National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USAStephanie B Seminara - Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USADaniel Macarthur - Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USASteven A Moore - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAKoh-Ichiro Yoshiura - Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanJames F Gusella - Department of Genetics, Harvard Medical School, Boston, Massachusetts, USAJoseph A Marsh - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKJohn M Graham Jr - Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California, USAAngela E Lin - Medical Genetics, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, USANicholas Katsanis - Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USAPeter L Jones - Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USAWilliam F Crowley Jr - Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USAErica E Davis - Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USADavid R FitzPatrick - MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UKMichael E Talkowski - Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.49(2), pp.238-248
- DOI
- 10.1038/ng.3743
- PMID
- 28067909
- PMCID
- PMC5473428
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Publisher
- United States
- Grant note
- P01 GM061354 / NIGMS NIH HHS MC_U127527199 / Medical Research Council UL1 TR001102 / NCATS NIH HHS MR/M02122X/1 / Medical Research Council T32 HD007396 / NICHD NIH HHS MC_U127561093 / Medical Research Council R01 HD043341 / NICHD NIH HHS F32 HD085857 / NICHD NIH HHS UM1 HG008900 / NHGRI NIH HHS U54 NS053672 / NINDS NIH HHS U54 HD060848 / NICHD NIH HHS MC_PC_U127561093 / Medical Research Council P50 DK096415 / NIDDK NIH HHS K23 HD073304 / NICHD NIH HHS P50 HD028138 / NICHD NIH HHS MC_PC_U127527199 / Medical Research Council R01 AR062587 / NIAMS NIH HHS R01 HD081256 / NICHD NIH HHS K23 HD077043 / NICHD NIH HHS R00 MH095867 / NIMH NIH HHS MC_PC_U127574433 / Medical Research Council
- Language
- English
- Date published
- 02/2017
- Academic Unit
- Occupational and Environmental Health; Pathology
- Record Identifier
- 9984047690502771
Metrics
11 Record Views