Myotonic Dystrophy Foundation

Print this page

What is a gene?

A gene is a stretch of DNA (the genetic material in the body) that carries the instructions on how to make a specific protein product. These proteins carries out the functions of the body: there are genes that control eye color, genes that make proteins to break down food in the stomach, and genes that encode enzymes that regulate how cells grow.

When the DNA of a gene is altered, a mutation is said to have occurred. Some mutations are benign and cause no significant change to the proteins produced from the gene (e.g. blue v. brown eye color). Others cause deficient or defective proteins to be produced, sometimes leading to disease symptoms (e.g. some people do not have the enzymes to digest milk; cancer can occur when control of cell growth is disrupted).

How are genes transmitted?

Genes are physically located along the chromosomes that are present in each cell in a person’s body. It is estimated that each cell contains more than 25,000 different genes that regulate the body’s various functions.

Every person has 23 pairs of chromosomes, one set received from each parent. This means each cell in the body has two copies of any given gene, one from that person’s mother and one from hid or her father. Both copies of a gene give directions to the cell on how to produce the particular product of that gene (i.e. the protein it encodes).

Sex cells (i.e., egg and sperm) are the only cells in the body that do not have two sets of chromosomes. During the development of an egg or sperm, a process called meiosis occurs and the 23 pairs of chromosomes split. As a result, each egg or sperm contains only one set of the chromosomes. When an egg is fertilized, the resulting zygote then has two complete sets of chromosomes and, therefore, two copies of each gene (one from the egg and one from the sperm).

Of the 23 pairs of chromosomes, one pair (called the sex chromosomes or X and Y) are responsible for determination of gender. Females have two copies of the X chromosomes (XX) and males have one copy of each type of sex chromosome (XY). XX mothers always pass on an X chromosome to their children. XY fathers can either pass on the X chromosome (in which case they have a daughter, XX) or a Y chromosome (in which case they have a son, XY).

The remaining chromosomes are called autosomes and are numbered from 1 to 22. They are not involved in determination of gender. A parent passes on one of the two chromosomes with equal frequency. Sons and daughters are equally likely to inherit either chromosome. The mutations for Myotonic Dystrophy Type 1 (DM-1) and Myotonic Dystrophy Type 2 (DM-2) occur on two different autosomes (chromosome 19 and chromosomes 3, respectively).

How is the myotonic dystrophy mutation transmitted?

Both Myotonic Dystrophy Type 1 (DM-1) and Myotonic Dystrophy Type 2 (DM-2) are transmitted by autosomal dominant mutations.

• Autosomal means the mutation is located on an autosome (i.e., a non sex-determining chromosome) and is therefore passed on to sons and daughters with equal frequency. In contrast, a sex-linked mutations show marked bias in transmission. For example, mutations located on the Y chromosome are passed on only to sons.

• A dominant mutation means that one copy of the mutated gene is sufficient to cause the disease. Affected individuals typically inherit the disease-causing gene from only one parent. In contrast, a recessive mutation requires both copies of a gene to carry the mutation. Therefore, both parents must carry a copy of the mutated gene to have a child with a recessive disorder.

In nearly all cases, patients with DM have one normal copy of the DM gene and one copy with the mutation. This means affected individuals have a 50% chance of passing on the mutated gene to their child. Individuals who receive the mutated gene will have DM (although they may not yet exhibit symptoms). Those that do not inherit the mutated gene will never develop the disease.

A recent study suggested that all affected individuals can be traced back to just one or two people who had the original mutations, thousands of years ago. Unlike some other genetic diseases, the mutations causing DM do not occur spontaneously (e.g., because of damage from radiation or certain chemicals). All cases appear to have been inherited from the common ancestor(s).

Myotonic dystrophy is a triplet repeat disease. What does that mean?

DNA is a very long chain of millions of chemical units, called nucleotide bases. The chromosomes in one cell contain roughly 3 billion of these nucleotides, linked together in long stretches that are then packaged into the 23 chromosomes. There are four different forms of nucleotides (adenine (A), cytosine(C), guanine (G), and thymine (T)). The order of the nucleotides is like a sentence that is “read” by the cell machinery and which tells the cell how a specific protein should be produced.

In certain genes, a small stretch of DNA containing three nucleotides (a triplet) is repeated over and over. This repeated DNA structure occurs normally, but when it expands too much it becomes unstable; errors can occur during DNA replication that cause the number of triplets to increase, expanding the repeat length. Diseases that result from such expanded repeats are called “triplet repeat diseases,” and include myotonic dystrophy (DM), Huntington’s disease, spinal and bulbar muscular atrophy (SBMA), and fragile X syndrome.

In DM-1, expansion of a CTG repeat disrupts the Dmpk (dystrophia-myotonica protein kinase) gene on chromosome 19. However, in DM-2, the repeated sequence is a four nucleotide repeat, CCTG in the Znf9 (zinc finger protein 9) gene on chromosome 3. Because DM-2 was recognized as a distinct form only relatively recently, myotonic dystrophy as a whole is still referred to as triplet repeat disorder.

How does the mutation cause the symptoms of myotonic dystrophy?

Genes direct the production of proteins through a two-step process:

• transcription, where a transient copy of the gene (RNA) is made in the cell nucleus

• translation, where that copy leaves the nucleus and enters the cytoplasm (the portion of the cell outside the nucleus) to direct the assembly of amino acids into a protein.

In DM, the mutated genes produce abnormal versions of the RNA. These versions contain the expanded repeats that cannot leave the nucleus. Instead, they clump together in toxic masses, called nuclear foci, which absorb factors responsible for the processing of as many as 20 other proteins. As a result, these multiple proteins remain in the form normally seen in developing fetuses, rather than being processed into the mature form required for proper cell function. It is these secondary proteins that cause of range of symptoms seen in DM.

How does the number of repeats influence disease symptoms?

The number of repeats an individual has is roughly predictive of their disease status. The table below shows the number of repeats seen in healthy individuals, those carrying the pre-mutation (i.e., those who can pass on the disease but are unlikely to ever exhibit symptoms), and those with DM.

However, the expanded repeats are erratic, with the number varying between individuals in the same family and even between tissues in the same individual. The number can also change over the lifespan of one individual.

In DM-1, the number of repeats tends to correlate with the severity of the symptoms: a lower number of repeats is generally seen in patients with a milder form of the disease, while a higher number can reflect more complicated disease status. As well, a higher number is often associated with earlier onset of symptoms. In DM-2, the relationship between repeat count and disease state is less direct. In both DM-1 and DM-2, many other genetic and environmental factors influence disease symptoms. Repeat count should not be considered definitively predictive of an individual’s prognosis.

The number of repeats tends to increase when the disorder is passed on to children, through a process called anticipation. Anticipation is a characteristic of most expanded repeat diseases. In DM-1, symptoms tend to be more severe and occur at a younger age in successive generations within a family as the repeat count increases. In DM-2, the repeat counts increase over successive generations; however, the increase in severity and earlier onset of symptoms is less apparent.

© Myotonic Dystrophy Foundation. All rights reserved.

• About Us
• Site Map
• User Agreement
• Contact