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Many faces of SMCHD1

Nature Genetics volume 49, pages 176–178 (2017)Cite this article

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The chromatin scaffolding protein SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) was previously shown to have diverse roles in X-chromosome inactivation, imprinting and double-strand break repair, and mutations in SMCHD1 contribute to a type of muscular dystrophy. Now, development of the nose and eyes is added to its list of functions.

The idea that genes may be co-opted into diverse roles through evolution is familiar to geneticists— it is termed developmental pleiotropy. The corollary is that mutations in genes can present with multifarious phenotypes, depending on the mechanism of action of the mutation. For example, dominant FGFR1 mutations cause abnormal development of the olfactory tract, skeletal malformations or holoprosencephaly according to whether the mutation acts as a haploinsufficiency, gain-of-function or dominant-negative change, respectively1. In this issue, studies conducted independently by Mark Talkowski, David FitzPatrick, Erica Davis and colleagues (page 238) and by Jeanne Amiel, Bernd Wollnik, Bruno Reversade and colleagues (page 249) present a striking example of such developmental pleiotropy2,3. Heterozygous mutations in SMCHD1 were previously shown to contribute, through a complex epigenetic mechanism, to a form of progressive muscular dystrophy, facioscapulohumeral muscular dystrophy type 2 (FSHD2; refs. 4,5). This new work now demonstrates that mutations of SMCHD1 cause severe malformations of the human nose, olfactory tract and eyes (Bosma arhinia microphthalmia syndrome; BAMS). Adding further intrigue, the two publications come to apparently contradictory conclusions about the mechanism of action of these mutations: whereas Shaw et al.2 support a loss- of-function mechanism, Gordon et al.3 favor a gain-of-function mechanism. Perhaps these conclusions are not as contradictory as they might first appear.

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Figure 1: Possible mechanisms of BAMS-associated mutations contrasted with those of FSHD2-associated mutations.

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  1. Andrew O. M. Wilkie is at the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.,

    Andrew O M Wilkie

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Wilkie, A. Many faces of SMCHD1. Nat Genet 49, 176–178 (2017). https://doi.org/10.1038/ng.3776

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