Gene of the Month – January: SMCHD1

SMCHD1 encodes the structural maintenance of chromosomes flexible hinge domain containing 1 protein, a member of the large SMC protein family. It is involved in epigenetic regulation of various genes and plays a role in X chromosome inactivation and DNA damage repair. It has been known that SMCHD1 mutations cause facioscapulohumeral muscle dystrophy type 2 (FSHD 2), a muscle weakness disorder that affects primarily the face and the shoulder girdle. Now a new function of the gene has been uncovered in a whole different area: the proper development of the nose.

Two recent articles published in Nature Genetics report on the identification of disease-causing de novo SMCHD1 mutations in patients presenting with arhinia, either in isolated form or, in combination with eye malformations, as part of Bosma arhinia microphthalmia syndrome. The genetic background for this very rare disorder in which the nose is either absent or developed incompletely has so far been elusive. Functional analyses performed in these recent studies also suggest that the mutations in the patients with arhinia lead to an increase in SMCHD1 protein function – in contrast to the loss-of-function mutations previously described to cause FSHD 2. With these studies, the researchers provide an example of how – depending on their type and functional effect – mutations in the same gene may bring about diverse disorders involving entirely different tissues and organs. Furthermore, these new findings may be useful in the development of novel approaches for the treatment of FSHD.