Tubular aggregate myopathy is a disorder that primarily affects the skeletal muscles, which are muscles the body uses for movement. This disorder causes muscle pain, cramping, or weakness that begins in childhood and worsens over time. The muscles of the lower limbs are most often affected, although the upper limbs can also be involved. Affected individuals can have difficulty running, climbing stairs, or getting up from a squatting position. The weakness may also lead to an unusual walking style (gait). Some people with this condition develop joint deformities (contractures) in the arms and legs.

Skeletal muscles are normally made up of two types of fibers, called type I and type II fibers, in approximately equal quantities. Type I fibers, also called slow twitch fibers, are used for long, sustained activity, such as walking long distances. Type II fibers, also known as fast twitch fibers, are used for short bursts of strength, which are needed for activities such as running up stairs or sprinting. In people with tubular aggregate myopathy, type II fibers waste away (atrophy), so affected individuals have mostly type I fibers. In addition, proteins build up abnormally in both type I and type II fibers, forming clumps of tube-like structures called tubular aggregates. Tubular aggregates can occur in other muscle disorders, but they are the primary muscle cell abnormality in tubular aggregate myopathy.

Tubular aggregate myopathy can be caused by mutations in the STIM1 gene. The protein produced from this gene is involved in controlling the entry of positively charged calcium atoms (calcium ions) into cells. The STIM1 protein recognizes when calcium ion levels are low and stimulates the flow of ions into the cell through special channels in the cell membrane called calcium-release activated calcium (CRAC) channels. In muscle cells, the activation of CRAC channels by STIM1 is thought to help replenish calcium stores in a structure called the sarcoplasmic reticulum. STIM1 may also be involved in the release of calcium ions from the sarcoplasmic reticulum. This release of ions stimulates muscle tensing (contraction).

The STIM1 gene mutations involved in tubular aggregate myopathy lead to production of a STIM1 protein that is constantly turned on (constitutively active), which means it continually stimulates calcium ion entry through CRAC channels regardless of ion levels. It is unknown how constitutively active STIM1 leads to the muscle weakness characteristic of tubular aggregate myopathy. Evidence suggests that the tubular aggregates are composed of proteins that are normally part of the sarcoplasmic reticulum. Although the mechanism is unknown, some researchers speculate that the aggregates are the result of uncontrolled calcium levels in muscle cells, possibly due to abnormal STIM1 activity.

Mutations in other genes, some of which have not been identified, are also thought to cause some cases of tubular aggregate myopathy.

Normal Function

The STIM1 gene provides instructions for making a protein called stromal interaction molecule 1 (STIM1). The STIM1 protein is involved in controlling the entry of positively charged calcium atoms (calcium ions) into cells when levels of the ions are low, specifically through channels called calcium-release activated calcium (CRAC) channels. The flow of calcium ions through CRAC channels triggers signaling within cells that plays a role in many cellular functions including control of gene activity, cell growth and division, and immune function.

STIM1 is found in the membrane of a cellular structure called the endoplasmic reticulum (ER), which, among other functions, stores calcium in cells. STIM1 recognizes when calcium levels in the ER are low and stimulates changes in the cell that allow STIM1 to attach (bind) to a protein called ORAI1 in the cell membrane. This protein, which is part of the CRAC channel, forms a hole (pore) in the cell membrane through which calcium ions can flow. STIM1 binding triggers the flow of calcium ions into the cell through the channel. STIM1 also likely plays a role in the process that stops the flow of calcium ions when enough calcium has entered.

STIM1 is also found in the sarcoplasmic reticulum, a structure similar to the ER that is found in muscle cells. This structure plays a major role in muscle contraction and relaxation by storing and releasing calcium ions. The STIM1 protein is thought to help replenish calcium stores in the sarcoplasmic reticulum through CRAC channels. It may also be involved in the release of calcium ions from the sarcoplasmic reticulum, which stimulates muscle contraction.

Health Conditions Related to Genetic Changes

Stormorken syndrome

A mutation in the STIM1 gene causes Stormorken syndrome, a rare condition characterized by a low number of blood cells called platelets (thrombocytopenia) and consequent bleeding problems, a muscle disorder called tubular aggregate myopathy (described below), and other abnormalities.

The mutation involved in this condition changes a single protein building block (amino acid) in the STIM1 protein, replacing the amino acid arginine with the amino acid tryptophan at protein position 304 (written as Arg304Trp or R304W). This change occurs in a region of the protein that is thought to be involved in keeping it turned off when calcium ion levels are high. As a result of this change, the altered STIM1 protein is constantly turned on (constitutively active), continually stimulating calcium ion entry through CRAC channels regardless of ion levels in the ER.

Because the genetic change enhances the activity of the protein, it is described as a "gain-of-function" mutation. Researchers suggest that the abnormal ion flow in platelets causes the cells to break down earlier than usual, leading to thrombocytopenia and bleeding problems in people with Stormorken syndrome. It is unknown how constitutively active STIM1 leads to the other features of the disorder.

Tubular aggregate myopathy

At least five gain-of-function mutations cause tubular aggregate myopathy without the other features of Stormorken syndrome (described above). In this disorder, proteins build up abnormally in muscle cells, forming clumps of tube-like structures called tubular aggregates. Tubular aggregate myopathy causes muscle pain, cramping, or weakness that worsens over time.

The mutations involved in this condition change single amino acids in STIM1, specifically in the region of the protein used for sensing calcium ion levels. Like the gain-of-function mutation that causes Stormorken syndrome, these mutations lead to production of a constitutively active STIM1 protein that continually stimulates calcium ion flow through CRAC channels.

It is unclear how abnormal ion flow leads to tubular aggregate myopathy. Evidence suggests that the tubular aggregates are composed of proteins that are normally part of the sarcoplasmic reticulum. Although the mechanism is unknown, some researchers speculate that the aggregates are the result of uncontrolled calcium levels in muscle cells, possibly due to abnormal STIM1 activity.

Researchers are not sure why another gain-of-function mutation causes the additional signs and symptoms of Stormorken syndrome.

Other disorders

At least three mutations in the STIM1 gene cause an immune system disorder called primary immunodeficiency 10. Because of immune system problems, individuals with this condition have recurrent infections that can be life-threatening. The mutations that cause primary immunodeficiency 10 are known as "loss-of-function" mutations because they reduce or eliminate the function of the STIM1 protein. Without stimulation by STIM1, calcium ion flow through CRAC channels is impaired, which hinders the ability of immune system cells to fight infections.

Other Names for This Gene

• D11S4896E
• GOK
• IMD10
• STRMK
• TAM
• TAM1

Genomic Location

• 25% chance to be affected
• 50% chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not a carrier

• thoroughly evaluating the family history
• addressing questions and concerns
• assessing recurrence risks
• facilitating genetic testing if desired