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

2017 | journal article. A publication with affiliation to the University of Göttingen.

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​De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development​
Gordon, C. T.; Xue, S.; Yigit, G. ; Filali, H.; Chen, K.; Rosin, N.   & Yoshiura, K.-i. et al.​ (2017) 
Nature Genetics49(2) pp. 249​-255​.​ DOI: https://doi.org/10.1038/ng.3765 

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Authors
Gordon, Christopher T.; Xue, Shifeng; Yigit, Gökhan ; Filali, Hicham; Chen, Kelan; Rosin, Nadine ; Yoshiura, Koh-ichiro; Oufadem, Myriam; Beck, Tamara J.; McGowan, Ruth; Magee, Alex C.; Altmüller, Janine; Dion, Camille; Thiele, Holger; Gurzau, Alexandra D; Nürnberg, Peter; Meschede, Dieter; Mühlbauer, Wolfgang; Okamoto, Nobuhiko; Varghese, Vinod; Irving, Rachel; Sigaudy, Sabine; Williams, Denise; Ahmed, S. Faisal; Bonnard, Carine; Kong, Mung Kei; Ratbi, Ilham; Fejjal, Nawfal; Fikri, Meriem; Elalaoui, Siham Chafai; Reigstad, Hallvard; Bole-Feysot, Christine; Nitschké, Patrick; Ragge, Nicola; Lévy, Nicolas; Tunçbilek, Gökhan; Teo, Audrey S. M.; Cunningham, Michael L.; Sefiani, Abdelaziz; Kayserili, Hülya; Murphy, James M.; Chatdokmaiprai, Chalermpong; Hillmer, Axel M.; Wattanasirichaigoon, Duangrurdee; Lyonnet, Stanislas; Magdinier, Frédérique; Javed, Asif; Blewitt, Marnie E.; Amiel, Jeanne; Wollnik, Bernd ; Reversade, Bruno
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.
Issue Date
2017
Journal
Nature Genetics 
Project
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | D02: Neue Mechanismen der genomischen Instabilität bei Herzinsuffizienz 
Working Group
RG Wollnik 
ISSN
1061-4036
Language
English

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