The SMCHD1/LRIF1 pathway

The Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1, MIM614982) is an evolutionarily conserved chromatin-binding protein involved in epigenetic silencing. SMCHD1 was first discovered to be critical for X-inactivation in mammals since homozygous mutant female mice die by mid-gestation while males remain healthy and fertile2. Subsequently SMCHD1 was also documented to regulate the expression of mono-allelically expressed and imprinted genes. 

Germline mutations in SMCHD1 have been implicated in two very distinct Mendelian human diseases. Haploinsufficiency of SMCHD1 is responsible for facioscapulohumeral dystrophy type 2 (FSHD2, MIM158901), where the monoallelic depletion of SMCHD1 causes hypomethylation of the D4Z4 repeat region and subsequent expression of DUX4 which is toxic to muscle lineages. More recently, de novo missense mutations in the GHKL ATPase domain of SMCHD1 have been shown to cause a striking craniofacial disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS, MIM603457) which is characterized by the congenital absence of a nose and its associated structures. 

The ancestral function of SMCHD1 involves chromatin organization in the maternal germline where is presence allows to silence HOX genes together with its binding partner LRIF1. When both genes are inactivated in mothers, HOX epimutations ensues triggering homeotic transformations in genetically wildtype offspring.