SMCHD1

SMCHD1 stands for structural maintenance of chromosomes flexible hinge domain containing 1. It is a human protein encoded by the SMCHD1 gene and a member of the structural maintenance of chromosomes (SMC) family. SMCHD1 proteins are large chromatin regulators characterized by a flexible hinge domain and an ATPase region. They participate in shaping chromatin architecture and epigenetic gene silencing.

SMCHD1 contributes to the maintenance of gene silencing at several genomic loci, including the inactive X chromosome in female mammals, and to imprinting at autosomal regions. It promotes higher‑order chromatin compaction and helps preserve DNA methylation at specific repeats, such as the D4Z4 macrosatellite on 4q35. The protein is thought to be recruited to silenced chromatin by XIST RNA and to stabilize long‑range chromatin interactions that suppress transcription.

Clinical significance: Pathogenic variants in SMCHD1 cause facioscapulohumeral muscular dystrophy type 2 (FSHD2), an autosomal dominant muscular dystrophy. In FSHD2, SMCHD1 mutations act in combination with a permissive D4Z4 haplotype on chromosome 4 (4q35), leading to hypomethylation of D4Z4 repeats and derepression of the DUX4 gene in muscle. The disease exhibits variable penetrance and expressivity. Beyond FSHD2, SMCHD1 continues to be studied for its broader role in epigenetic regulation and chromatin organization, with research focused on how altered SMCHD1 function affects genome regulation.