The mechanism of FSHD
Let's learn about facioscapulohumeral muscular dystrophy (FSHD)
What is FSHD?
FSHD (facioscapulohumeral muscular dystrophy) is one type of muscular dystrophy.
FSHD stands for Facio (face), Scapulo (shoulder blade), Humeral (upper arm), and Muscular Dystrophy, and as the name suggests, it causes weakness in the muscles around the face and shoulder blades. Weak facial muscles can make it difficult to whistle, smile properly, or close the eyelids from childhood. Weak shoulder blade muscles can cause the shoulder blades to protrude and make it difficult to raise the arms high. Other symptoms include weak abdominal muscles causing the abdomen to protrude and weak leg muscles leading to tripping.
As the disease progresses, other muscles, such as those in the fingers and thighs, may weaken, and some people may require a wheelchair. Additionally, muscle weakness often varies significantly between the left and right sides of the body.
The progression of FSHD varies greatly from person to person. Some people require a wheelchair from childhood, while others do not notice the disease until middle age. FSHD can also affect areas other than the muscles. Some people experience hearing loss or abnormalities in the blood vessels at the back of the eyes.
Causes of FSHD
⚫︎What is DNA?
FSHD is a disease of the DNA. So what exactly is DNA?
The human body is made up of countless cells. Each cell contains a nucleus, which houses DNA. Within this DNA are sections that contain the blueprints for proteins, and these sections are called genes. The proteins produced from these genes form the structure of the human body. Therefore, DNA is often referred to as the “blueprint of the body.”
⚫︎There are various types of muscular dystrophy
Muscular dystrophy is a genetic disorder caused by a mutation in DNA. In many genetic disorders, genes undergo changes, preventing the body from producing normal proteins and leading to disease. There are various types of muscular dystrophy, each with different causes.
• The mechanism of Duchenne muscular dystrophy
For example, the dystrophin gene produces dystrophin protein, which strengthens muscles. If the dystrophin gene undergoes a mutation, the body cannot produce dystrophin protein, leading to weakened muscles. As a result, this condition is known as Duchenne muscular dystrophy.
The mechanism of FSHD
So, what about FSHD? FSHD is completely the opposite, caused by the overactivity of the DUX4 protein produced by the DUX4 gene. This DUX4 protein is toxic to muscles.
The DUX4 protein is not normally produced in muscles. This is because the DNA sequence adjacent to the DUX4 gene, known as DUXZ4, suppresses the production of the DUX4 protein.
In FSHD, the length of the D4Z4 sequence is shorter than normal. As a result, the DUX4 gene cannot be suppressed, leading to the production of DUX4 protein.
It is believed that this DUX4 protein damages the muscles, resulting in FSHD.
In fact, D4Z4 is not the only factor that suppresses the activity of the DUX4 gene. For example, the SMCHD1 gene and many other genes produce proteins that bind to D4Z4, thereby cooperating to suppress the DUX4 gene.
Therefore, it is believed that when one of the genes responsible for suppressing the DUX4 gene is significantly missing or when several genes are slightly deficient, the DUX4 gene can no longer be suppressed, leading to FSHD.
For example, individuals with a very short D4Z4 sequence alone develop FSHD (FSHD type 1). Additionally, individuals with a slightly shorter D4Z4 sequence who also have mutations in the SMCHD1 gene are known to develop FSHD (FSHD type 2). Furthermore, it is believed that there are still other causes of FSHD.
Patterns of inheritance
FSHD can be passed on to children. Just as there is no single cause of FSHD, there is no single pattern of inheritance.
・FSHD type 1
People who have a “very short” D4Z4 are affected by FSHD. This is called FSHD type 1. The probability of this very short D4Z4 being passed on to children is the same as the probability of it not being passed on.
※Haplotype
The haplotype examined in DNA testing is linked to this short D4Z4. This haplotype also influences the inheritance of FSHD. However, even if it is genetically inherited, whether or not the disease develops or the severity of symptoms may vary between parents and children.
・FSHD Type 2
Unlike FSHD Type 1, some individuals with a slightly shorter D4Z4 may develop FSHD.This is referred to as FSHD Type 2.
It was previously believed that a slightly shorter D4Z4 alone did not cause FSHD.
However, recent studies have shown that individuals with a slightly shorter D4Z4 may develop FSHD Type 2 due to changes in other genes. Genes that may influence this include the SMCHD1 gene, DNMT3B gene, and LRIF1 gene.
In the case of FSHD type 2, even if a slightly shorter D4Z4 is inherited by a child, it does not necessarily mean that the child will develop FSHD. Both the slightly shorter D4Z4 and changes in other genes such as the SMCHD1 gene must be present for FSHD type 2 to develop, and the probability of this occurring is lower than for FSHD type 1.
・Mosaicism
During the development of an embryo in the womb, there is a chance that D4Z4 may suddenly become shorter in certain cells. As a result, the individual will have a body composed of cells with both long and short D4Z4. This phenomenon is called mosaicism.
Individuals with mosaicism also have sperm and eggs that carry mosaicism. In other words, sperm and eggs may contain both long and short D4Z4 segments. The pattern of this mixture varies from person to person, so it is unclear what percentage of children born to individuals with mosaicism will develop FSHD.
DNA testing
FSHD can be diagnosed through DNA testing. The test is performed using DNA extracted from blood.
DNA testing involves measuring the length of D4Z4 using Southern blotting or reading the sequence of SMCHD1 using sequencing methods.
However, this DNA test is only available to individuals exhibiting symptoms of FSHD. It is not available to healthy individuals or fetuses in the womb.
There are hospitals overseas where such individuals can undergo testing.
For more detailed information about FSHD, please refer to the following website, which provides explanations by specialized institutions.
“Genetic Diagnosis of Facioscapulohumeral Muscular Dystrophy”
(National Center of Neurology and Psychiatry, National Institute of Mental Health, Department of Disease Research I)
https://www.ncnp.go.jp/nin/guide/r1/FSHD.html
“Diagnostic Procedures for Facial-scapular-brachial Muscular Dystrophy”
(MD Clinical Station for Doctors “Research and Study on the Standardization of Medical Care for Muscular Dystrophy” Team)