SMCHD1 gene

The SMCHD1 gene provides instructions for a protein that regulates gene activity through DNA methylation, playing a critical role in development and muscle health.

Normal Function

The SMCHD1 gene provides instructions for making a protein that is involved in regulating gene activity by altering the structure of DNA. Specifically, the SMCHD1 protein is associated with DNA methylation, which is the addition of methyl groups to DNA molecules. The addition of methyl groups is associated with the turning off (silencing) of genes.

The SMCHD1 protein is involved in a process called X-inactivation. Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated. The SMCHD1 protein appears to be involved in the hypermethylation of certain areas of DNA called CpG islands, which is critical for inactivation of the X chromosome. The SMCHD1 protein then remains attached to the inactive X chromosome to help keep it inactivated.

The SMCHD1 protein also plays a role in hypermethylation of a region near the end of chromosome 4 called D4Z4. Because the D4Z4 region is hypermethylated, the DUX4 gene is silenced in most adult cells and tissues.

The SMCHD1 protein appears to play a role in normal development of the nose, eyes, and other structures of the head and face and seems to be involved in repairing damaged DNA.

Health Conditions Related to Genetic Changes

Bosma arhinia microphthalmia syndrome

At least nine SMCHD1 gene mutations have been found to cause Bosma arhinia microphthalmia syndrome (BAMS). Individuals with this rare condition have an abnormally small or absent nose (arhinia), unusually small eyes (microphthalmia), and a shortage of certain hormones that direct sex development (hypogonadotropic hypogonadism).

The gene mutations involved in BAMS change single protein building blocks in the SMCHD1 protein. SMCHD1 gene mutations may lead to abnormal silencing of genes involved in development of the head and face. Problems with nasal development may affect gonadotropin-releasing hormone (GnRH) neurons, which are nerve cells that control the release of reproductive hormones.

Facioscapulohumeral muscular dystrophy

Dozens of mutations in the SMCHD1 gene have been found to cause facioscapulohumeral muscular dystrophy, a disorder characterized by muscle weakness and wasting (atrophy) that worsens slowly over time. Two forms of the disorder have been described: type 1 (FSHD1) and type 2 (FSHD2).

SMCHD1 gene mutations cause most cases of FSHD2. These mutations reduce the amount of SMCHD1 protein available to silence the D4Z4 region. This region has fewer methyl groups than usual (hypomethylation), which is associated with impaired silencing of the DUX4 gene in cells and tissues where it is usually turned off. However, hypomethylation of the D4Z4 region results in facioscapulohumeral muscular dystrophy only when it occurs in people who also have at least one copy of chromosome 4 that is described as "permissive."

Other disorders

SMCHD1 gene mutations have also been found in individuals with arhinia without other features of BAMS, which is referred to as isolated arhinia.

Other Names for This Gene

• KIAA0650
• SMC hinge domain-containing protein 1
• structural maintenance of chromosomes flexible hinge domain-containing protein 1