Journal Article

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

Yigit, Gökhan, Wollnik, Bernd, Ahmed, S Faisal, Reversade, Bruno, Kayserili, Hülya, Altmüller, Janine, Murphy, James M, Magdinier, Frédérique, Nitschké, Patrick, Thiele, Holger, Elalaoui, Siham Chafai, Dion, Camille, Tunçbilek, Gökhan, McGowan, Ruth, Williams, Denise, Fejjal, Nawfal, Filali, Hicham, Reigstad, Hallvard, Kong, Mung Kei, Meschede, Dieter, Bonnard, Carine, Ratbi, Ilham, Lévy, Nicolas, Blewitt, Marnie E, Beck, Tamara J, Gurzau, Alexandra D, Yoshiura, Koh-ichiro, Teo, Audrey S M, Rosin, Nadine, Oufadem, Myriam, Irving, Rachel, Sigaudy, Sabine, Varghese, Vinod, Hillmer, Axel M, Chen, Kelan, Mühlbauer, Wolfgang, Magee, Alex C, Gordon, Christopher T, Fikri, Meriem, Bole-Feysot, Christine, Sefiani, Abdelaziz, Lyonnet, Stanislas, Nürnberg, Peter, Ragge, Nicola, Cunningham, Michael L, Okamoto, Nobuhiko, Wattanasirichaigoon, Duangrurdee, Chatdokmaiprai, Chalermpong, Javed, Asif, Amiel, Jeanne, Xue, Shifeng

2017

Overview

Jeanne Amiel, Bernd Wollnik, Bruno Reversade and colleagues report de novo missense mutations in SMCHD1 in patients with Bosma arhinia microphthalmia syndrome (BAMS) and isolated arhinia. Mechanistic studies support a key role for SMCHD1 in nasal development and suggest that the mutations in patients may function via a gain-of-function mechanism. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/136/1455 / 631/208/1516 / 631/208/207 / Agriculture / Animal Genetics and Genomics / Animals / Biochemical tests / Biomedicine / Cancer Research / Career development planning / Cell Line / Cellular signal transduction / Child, Preschool / Choanal Atresia / Choanal Atresia - genetics / Chromosomal Proteins, Non-Histone / Chromosomal Proteins, Non-Histone - genetics / Chromosomes / Consortia / Councils / Defects / Deoxyribonucleic acid / Development and progression / Development Biology / DNA / DNA methylation / Dystrophy / Embryology and Organogenesis / Epigenesis, Genetic / Epigenesis, Genetic - genetics / Female / Gene expression / Gene Function / Gene mutation / Genetic aspects / Genetic Predisposition to Disease / Genetic Predisposition to Disease - genetics / Genetics / Health aspects / Human Genetics / Humans / letter / Life Sciences / Male / Males / Mice / Mice, Inbred C57BL / Microphthalmos / Microphthalmos - genetics / Muscular Dystrophy, Facioscapulohumeral / Muscular Dystrophy, Facioscapulohumeral - genetics / Mutation / Mutation, Missense / Mutation, Missense - genetics / Nose / Nose - abnormalities / Risk factors / Studies / Xenopus laevis / Xenopus laevis - genetics