title: De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
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.
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, Paris, France.|Paris Descartes, Sorbonne Paris Cité Université, Institut Imagine, Paris, France.
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authors.identifier: http://orcid.org/0000-0002-9300-8399
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authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
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authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, Paris, France.|Paris Descartes, Sorbonne Paris Cité Université, Institut Imagine, Paris, France.|Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Mohammed V University, Rabat, Morocco.
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authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
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authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
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authors.affiliation: Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, Paris, France.|Paris Descartes, Sorbonne Paris Cité Université, Institut Imagine, Paris, France.
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authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
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authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
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authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
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authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
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authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, Paris, France.|Paris Descartes, Sorbonne Paris Cité Université, Institut Imagine, Paris, France.|Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
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authors.affiliation: Human Genetics and Embryology Laboratory, Institute of Medical Biology, A*STAR, Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore.|Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey.|Department of Paediatrics, School of Medicine, National University of Singapore, Singapore.|Amsterdam Reproduction and Development, Academic Medical Centre and VU University Medical Center, Amsterdam, the Netherlands.
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mesh_terms: D000818:Animals; D002460:Cell Line; D002675:Child, Preschool; D002754:Choanal Atresia / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008850:Microphthalmos / Q000235:genetics*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D009666:Nose / Q000002:abnormalities*; D014982:Xenopus laevis / Q000235:genetics
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C578241:SMCHD1 protein, human