De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Christopher T Gordon^{1

2}, Shifeng Xue^{3

4}, Gökhan Yigit⁵, Hicham Filali^{1

2

6}, Kelan Chen^{7

8}, Nadine Rosin⁵, Koh-Ichiro Yoshiura⁹, Myriam Oufadem^{1

2}, Tamara J Beck⁷, Ruth McGowan¹⁰, Alex C Magee¹¹, Janine Altmüller^{12

13

14}, Camille Dion¹⁵, Holger Thiele¹², Alexandra D Gurzau^{7

8}, Peter Nürnberg^{12

14

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 Elalaoui^{6

26}, Hallvard Reigstad²⁷, Christine Bole-Feysot^{2

28}, Patrick Nitschké^{2

29}, Nicola Ragge^{22

30}, Nicolas Lévy^{15

21}, Gökhan Tunçbilek³¹, Audrey S M Teo³², Michael L Cunningham³³, Abdelaziz Sefiani^{6

26}, Hülya Kayserili³⁴, James M Murphy^{7

8}, Chalermpong Chatdokmaiprai³⁵, Axel M Hillmer³², Duangrurdee Wattanasirichaigoon³⁶, Stanislas Lyonnet^{1

2

37}, Frédérique Magdinier¹⁵, Asif Javed³², Marnie E Blewitt^{7

8}, Jeanne Amiel^{1

2

37}, Bernd Wollnik^{5

13}, Bruno Reversade^{3

4

34

38

39}

Affiliations

¹ Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, Paris, France.
² Paris Descartes, Sorbonne Paris Cité Université, Institut Imagine, Paris, France.
³ Human Genetics and Embryology Laboratory, Institute of Medical Biology, A*STAR, Singapore.
⁴ Institute of Molecular and Cell Biology, A*STAR, Singapore.
⁵ Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
⁶ Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Mohammed V University, Rabat, Morocco.
⁷ Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
⁸ Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
⁹ Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
¹⁰ West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK.
¹¹ Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
¹² Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
¹³ Institute of Human Genetics, University of Cologne, Cologne, Germany.
¹⁴ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
¹⁵ Aix Marseille Université, INSERM, Génétique Médicale et Génomique Fonctionnelle (GMGF), UMRS 910, Marseille, France.
¹⁶ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹⁷ Praxis für Humangenetik, Cologne, Germany.
¹⁸ Plastische und Ästhetische Chirurgie, ATOS Klinik München, Munich, Germany.
¹⁹ Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
²⁰ Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
²¹ Département de Génétique Médicale, Hôpital Timone Enfant, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
²² West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
²³ Developmental Endocrinology Research Group, University of Glasgow, RHC, Glasgow, UK.
²⁴ Service de Chirurgie Plastique Pédiatrique, Hôpital d'Enfants, CHU Ibn Sina, Mohammed V University, Rabat, Morocco.
²⁵ Service de Neuroradiologie, Hôpital des Spécialités, CHU Ibn Sina, Mohammed V University, Rabat, Morocco.
²⁶ Département de Génétique Médical, Institut National d'Hygiène, Rabat, Morocco.
²⁷ Neonatal Intensive Care Unit, Children's Department, Haukeland University Hospital, Bergen, Norway.
²⁸ Genomic Platform, INSERM UMR 1163, Institut Imagine, Paris, France.
²⁹ Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, Paris, France.
³⁰ Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
³¹ Department of Plastic, Reconstructive and Aesthetic Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey.
³² Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR, Singapore.
³³ University of Washington Department of Pediatrics, Division of Craniofacial Medicine and Seattle Children's Hospital Craniofacial Center, Seattle, Washington, USA.
³⁴ Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey.
³⁵ Plastic and Maxillofacial Surgery, Department of Surgery, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
³⁶ Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
³⁷ Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
³⁸ Department of Paediatrics, School of Medicine, National University of Singapore, Singapore.
³⁹ Amsterdam Reproduction and Development, Academic Medical Centre and VU University Medical Center, Amsterdam, the Netherlands.

PMID: 28067911
DOI: 10.1038/ng.3765

Free article

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Christopher T Gordon et al. Nat Genet. 2017 Feb.

Free article

. 2017 Feb;49(2):249-255.

doi: 10.1038/ng.3765. Epub 2017 Jan 9.

Authors

Affiliations

¹ Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, Paris, France.
² Paris Descartes, Sorbonne Paris Cité Université, Institut Imagine, Paris, France.
³ Human Genetics and Embryology Laboratory, Institute of Medical Biology, A*STAR, Singapore.
⁴ Institute of Molecular and Cell Biology, A*STAR, Singapore.
⁵ Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
⁶ Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Mohammed V University, Rabat, Morocco.
⁷ Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
⁸ Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
⁹ Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
¹⁰ West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK.
¹¹ Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
¹² Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
¹³ Institute of Human Genetics, University of Cologne, Cologne, Germany.
¹⁴ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
¹⁵ Aix Marseille Université, INSERM, Génétique Médicale et Génomique Fonctionnelle (GMGF), UMRS 910, Marseille, France.
¹⁶ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹⁷ Praxis für Humangenetik, Cologne, Germany.
¹⁸ Plastische und Ästhetische Chirurgie, ATOS Klinik München, Munich, Germany.
¹⁹ Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
²⁰ Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
²¹ Département de Génétique Médicale, Hôpital Timone Enfant, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
²² West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
²³ Developmental Endocrinology Research Group, University of Glasgow, RHC, Glasgow, UK.
²⁴ Service de Chirurgie Plastique Pédiatrique, Hôpital d'Enfants, CHU Ibn Sina, Mohammed V University, Rabat, Morocco.
²⁵ Service de Neuroradiologie, Hôpital des Spécialités, CHU Ibn Sina, Mohammed V University, Rabat, Morocco.
²⁶ Département de Génétique Médical, Institut National d'Hygiène, Rabat, Morocco.
²⁷ Neonatal Intensive Care Unit, Children's Department, Haukeland University Hospital, Bergen, Norway.
²⁸ Genomic Platform, INSERM UMR 1163, Institut Imagine, Paris, France.
²⁹ Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, Paris, France.
³⁰ Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
³¹ Department of Plastic, Reconstructive and Aesthetic Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey.
³² Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR, Singapore.
³³ University of Washington Department of Pediatrics, Division of Craniofacial Medicine and Seattle Children's Hospital Craniofacial Center, Seattle, Washington, USA.
³⁴ Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey.
³⁵ Plastic and Maxillofacial Surgery, Department of Surgery, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
³⁶ Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
³⁷ Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
³⁸ Department of Paediatrics, School of Medicine, National University of Singapore, Singapore.
³⁹ Amsterdam Reproduction and Development, Academic Medical Centre and VU University Medical Center, Amsterdam, the Netherlands.

PMID: 28067911
DOI: 10.1038/ng.3765

Abstract

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

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De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Affiliations

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Authors

Affiliations

Abstract

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases