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: Christopher T Gordon, Shifeng Xue, Gökhan Yigit, Hicham Filali, Kelan Chen, Nadine Rosin, Koh-Ichiro Yoshiura, Myriam Oufadem, Tamara J Beck, Ruth McGowan, Alex C Magee, Janine Altmüller, Camille Dion, Holger Thiele, Alexandra D Gurzau, Peter Nürnberg, Dieter Meschede, Wolfgang Mühlbauer, Nobuhiko Okamoto, Vinod Varghese, Rachel Irving, Sabine Sigaudy, Denise Williams, S Faisal Ahmed, Carine Bonnard, Mung Kei Kong, Ilham Ratbi, Nawfal Fejjal, Meriem Fikri, Siham Chafai Elalaoui, Hallvard Reigstad, Christine Bole-Feysot, Patrick Nitschké, Nicola Ragge, Nicolas Lévy, Gökhan Tunçbilek, Audrey S M Teo, Michael L Cunningham, Abdelaziz Sefiani, Hülya Kayserili, James M Murphy, Chalermpong Chatdokmaiprai, Axel M Hillmer, Duangrurdee Wattanasirichaigoon, Stanislas Lyonnet, Frédérique Magdinier, Asif Javed, Marnie E Blewitt, Jeanne Amiel, Bernd Wollnik, Bruno Reversade
• Journal: Nature genetics (Nat Genet) Vol. 49 Issue 2 Pg. 249-255 (Feb 2017) ISSN: 1546-1718 [Electronic] United States
• PMID: 28067911 (Publication Type: Journal Article)

Chemical References

• Chromosomal Proteins, Non-Histone
• SMCHD1 protein, human

Topics

• Animals
• Cell Line
• Child, Preschool
• Choanal Atresia (genetics)
• Chromosomal Proteins, Non-Histone (genetics)
• Epigenesis, Genetic (genetics)
• Female
• Genetic Predisposition to Disease (genetics)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Microphthalmos (genetics)
• Muscular Dystrophy, Facioscapulohumeral (genetics)
• Mutation, Missense (genetics)
• Nose (abnormalities)
• Xenopus laevis (genetics)