Facioscapulohumeral muscular dystrophy (FSHD) is a heritable muscle disorder characterized by the weakness and wasting of the muscles of the face, shoulder blades (scapula), and upper arms (humerus). Symptoms usually appear around age 20 and progress slowly. Around 20% of patients may need a wheelchair in the later stages of the disease.

FSHD and the DUX4 gene

FSHD is caused by the expression of a gene called DUX4 that should have been silenced after birth. DUX4 is normally only expressed during fetal development.

The DUX4 gene is situated on human chromosome 4, in an area called the D4Z4 region. This region contains 11 to 100 identical units of a specific sequence of DNA called D4Z4 repeats. Each of these repeats includes a single copy of the DUX4 gene.

There are two major mechanisms that complement each other in keeping the DUX4 gene silenced.

  • The D4Z4 region is tightly packed, or condensed, in all cells after birth because of the interactions between the D4Z4 repeats. Therefore, the DUX4 gene is not accessible for expression. Higher numbers of D4Z4 repeats means tighter packing of the D4Z4 region.
  • The DNA is made up of four nucleotides, or “letters” — adenine (A), guanine (G), cytosine (C), and thymine (T). The status of DNA methylation — high or low — is one of the mechanisms by which gene expression is regulated. Methyl groups are added by DNA-methylating enzymes to the cytosine residues in the DNA sequence. When a DNA region is highly methylated, gene expression is reduced or silenced. Conversely, when DNA methylation status is decreased, called hypomethylation, gene expression is generally higher. DNA methylation status depends on the activity of the DNA methylation enzymes.

Both of these mechanisms prevent the gene expression machinery from gaining access to the DUX4 gene.

In individuals with FSHD, alterations in the mechanisms that keep the gene silenced allow the production of DUX4 protein. This causes the symptoms of FSHD.

There are two types of this disorder, which are clinically indistinguishable: FSHD1 and FSHD2. Nearly 95% of patients are affected by FSHD1, while the remaining 5% have FSHD2. The two types of FSHD differ in the way DUX4 gene expression is allowed.

Inheritance of FSHD1

FSHD1 is inherited in an autosomal dominant manner, in which the individual inherits a misfunctioning chromosome 4 from one parent. It can be inherited from either the father or the mother. This chromosome 4 allows the expression of the DUX4 gene because of reduced numbers of D4Z4 repeats, or the hypomethylation of the D4Z4 region.

In most FSHD1 patients, the number of D4Z4 repeats is reduced substantially (1-10 repeats instead of 11-100) in one of the inherited chromosomes. This decondenses, or loosens, the D4Z4 region, allowing the expression of the DUX4 gene.

In some people with FSHD1, normal numbers of D4Z4 repeats (11-100) are observed in the parents. However, the children still develop FSHD because of reduced numbers of D4Z4 repeats. This can be explained in two ways:

  • De novo (new) reduction of D4Z4 repeats that occurs during development and that is not inherited from the parents
  • Genetic mosaicism, a phenomenon in which parents have two types of cells: some with reduced numbers of D4Z4 repeats, and others with normal numbers of D4Z4 repeats. In such a scenario, the reduced numbers of repeats may not be apparent when the parents are tested, but children inherit the chromosome 4 with reduced numbers of D4Z4 repeats. That results in the children manifesting the disease.

Inheritance of FSHD2

In individuals with FSHD2, the number of D4Z4 repeats is not altered or deleted. However, in 80% of FSHD2 patients, another gene, called SMCHD1 — or, structural maintenance of chromosomes flexible hinge domain containing region 1 — is mutated. The SMCHD1 protein is one of the DNA-methylating enzymes that adds methyl groups to the D4Z4 region. The mutation in the SMHCD1 gene causes hypomethylation in the D4Z4 region. This decondenses the DNA, and allows the expression of the DUX4 gene. This mode of inheritance is called digenic inheritance because a mutation in one gene, SMHCD1, causes the aberrant expression of another, the DUX4 gene.

In the remaining 20% of FSHD2 patients, the mutations in the SMCHD1 gene have not been identified. Because of that, the reason for hypomethylation in the D4Z4 region in these individuals is not yet known.

More severe cases

Some family members affected by FSHD have both FSHD1 and FSHD2 — reduced numbers of D4Z4 repeats as well as hypomethylation of the D4Z4 region. These individuals have more severe disease. They probably acquired reduced numbers of D4Z4 repeats from one parent, and a mutated SMCHD1 gene from the other.

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