Smchd1, or Structural Maintenance of Chromosomes Hinge Domain Containing Protein 1, is a large multidomain protein involved in epigenetic gene silencing. It shares domain organization similarities with SMC proteins like cohesin and condensin, affecting chromatin conformation, but is a non-canonical member of the family [1]. It has been linked to pathways related to genomic imprinting, X-chromosome inactivation, and DNA damage repair. Variations in the SMCHD1 gene are associated with two human disorders: facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphthalmia syndrome (BAMS) [1,2]. Mouse models have been crucial in understanding its function.

In mice, maternal Smchd1 is required for genomic imprinting, regulating the imprinted expression of ten genes [5]. It also prevents precocious activation of Hox genes post-implantation, and without it, posterior homeotic transformations occur in the embryo [6]. In terms of disease, loss-of-function mutations in Smchd1 in muscle fibers cause FSHD2 through derepression of the D4Z4 chromatin domain and aberrant expression of DUX4 [3]. Additionally, Smchd1 loss causes splicing alterations of DNMT3B, leading to hypomethylation and DUX4 overexpression, which is involved in FSHD pathogenesis [4].

In conclusion, Smchd1 plays essential roles in epigenetic gene silencing, genomic imprinting, and Hox gene regulation. The study of Smchd1 using KO/CKO mouse models has provided valuable insights into its functions and its association with FSHD, highlighting its importance in understanding the molecular mechanisms of this disease.