The more SMN1 and SMN2 genes you have in your cells, the more SMN protein your body can make.

SMA stems from a change in the SMN1 gene, most often a deletion or absence of a part of the gene called exon 7. The SMN1 gene gives the body instructions for making the SMN protein that keeps motor neurons healthy and able to carry messages from the brain and spinal cord to different parts of the body.

Without a working SMN1 gene, your baby cannot make enough SMN protein. As a result, motor neurons can get sick and die. This damages the connection between the brain and the muscles, leading to muscle weakness. The SMN2 gene also provides instructions for SMN protein. The amount of SMN protein that SMN2 can make depends on the number of copies of SMN2 a baby has. The more SMN2 copies, the more SMN protein and, usually, the milder the signs and symptoms.

Normal Function

The SMN1 gene provides instructions for making the survival motor neuron (SMN) protein. The SMN protein is found throughout the body, with highest levels in the spinal cord. This protein is one of a group of proteins called the SMN complex, which is important for the maintenance of specialized nerve cells called motor neurons. These cells are located in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract), which allows the body to move.

In cells, the SMN complex plays an important role in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. Messenger RNA begins as a rough draft (pre-mRNA) and goes through several processing steps to become a final, mature form. The SMN complex helps to assemble the cellular machinery needed to process pre-mRNA. The SMN complex is also important for the development of specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are required for the transmission of impulses between neurons and from neurons to muscles.

A small amount of SMN protein is produced from a gene similar to SMN1 called SMN2. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is functional; the other versions are smaller and quickly broken down.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Spinal muscular atrophy

Many mutations in the SMN1 gene have been found to cause spinal muscular atrophy. This condition is characterized by a loss of motor neurons that leads to weakness and wasting (atrophy) in muscles used for movement (skeletal muscles) that worsens with age. Spinal muscular atrophy has a wide range of severity. There are many types of spinal muscular atrophy that differ in age of onset and level of muscle functioning; however, there is overlap among the types. About 95 percent of individuals with spinal muscular atrophy have mutations that delete a piece of the SMN1 gene in both copies of the gene in each cell. As a result, SMN protein production is impaired. In about 5 percent of people with this disorder, one copy of the SMN1 gene is missing a section, and the other copy has a different kind of mutation that disrupts the production or function of the SMN protein.

Researchers suggest that a shortage of SMN protein leads to the inefficient assembly of the machinery needed to process pre-mRNA. A lack of mature mRNA, and subsequently the proteins needed for normal cell functioning, has damaging effects on motor neuron development and survival. The loss of motor neurons leads to the signs and symptoms of spinal muscular atrophy. However, it is unclear why these cells are particularly sensitive to a reduction in the amount of SMN protein. Some research findings indicate that a shortage of this protein impairs the formation and function of axons and dendrites, leading to the death of motor neurons.

Typically, people have two copies of the SMN1 gene and one to two copies of the SMN2 gene in each cell. However, the number of copies of the SMN2 gene varies, with some people having up to eight copies. Multiple copies of the SMN2 gene are usually associated with less severe features of the condition that develop later in life. The small amount of SMN protein produced by the SMN2 genes can help make up for the protein deficiency caused by SMN1 gene mutations. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy.

Other Names for This Gene

• BCD541
• SMA1
• SMA2
• SMA3
• SMA4
• SMN_HUMAN
• SMNT
• T-BCD541
• telomeric SMN

Genomic Location

Normal Function

The SMN2 gene provides instructions for making the survival motor neuron (SMN) protein. The SMN protein is found throughout the body, with highest levels in the spinal cord. This protein is one of a group of proteins called the SMN complex, which is important for the maintenance of specialized nerve cells called motor neurons. These cells are located in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract), which allows the body to move.

Several different versions of the SMN protein are produced from the SMN2 gene, but only one version (called isoform d) is full size and functional. The other versions are smaller and quickly broken down. The full-size protein made from the SMN2 gene is identical to the protein made from a similar gene called SMN1; however, only 10 to 15 percent of all functional SMN protein is produced from the SMN2 gene (the rest is produced from the SMN1 gene). Typically, people have two copies of the SMN1 gene and one to two copies of the SMN2 gene in each cell. However, the number of copies of the SMN2 gene varies, with some people having up to eight copies. The more SMN2 gene copies a person has, the more SMN protein they produce.

In cells, the SMN complex plays an important role in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. Messenger RNA begins as a rough draft (pre-mRNA) and goes through several processing steps to become a final, mature form. The SMN complex helps to assemble the cellular machinery needed to process pre-mRNA. The SMN complex is also important for the development of specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are required for the transmission of impulses between neurons and from neurons to muscles.

Health Conditions Related to Genetic Changes

Spinal muscular atrophy

Extra copies of the SMN2 gene do not cause spinal muscular atrophy, but they modify the severity of the disorder. This condition is characterized by a loss of motor neurons that leads to weakness and wasting (atrophy) in muscles used for movement (skeletal muscles) that worsens with age. Spinal muscular atrophy has a wide range of severity. There are many types of spinal muscular atrophy that differ in age of onset and level of muscle functioning; however, there is overlap among the types. All individuals with spinal muscular atrophy have mutations in both copies of the SMN1 gene. As a result, little or no SMN protein is produced from this gene. The SMN2 gene can help replace some of the missing SMN protein. In people with spinal muscular atrophy, having multiple copies of the SMN2 gene is usually associated with less severe features of the condition that develop later in life. Affected individuals with one or two functional copies of the SMN2 gene generally have severe muscle weakness that begins at birth or in infancy. Affected individuals with four or more copies of the SMN2 gene typically have mild muscle weakness that may not become noticeable until adulthood. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy.

Researchers suggest that a shortage of SMN protein leads to the inefficient assembly of the machinery needed to process pre-mRNA. A lack of mature mRNA and subsequently, the proteins needed for normal cell functioning, has damaging effects on motor neuron development and survival. The loss of motor neurons leads to the signs and symptoms of spinal muscular atrophy. However, it is unclear why these cells are particularly sensitive to a reduction in the amount of SMN protein. Some research findings indicate that a shortage of SMN protein impairs the formation and function of axons and dendrites, leading to the death of motor neurons. While the mechanism is not clear, it is apparent that increased SMN2 gene copy number leads to an increase in SMN protein production, which improves the function and survival of motor neurons and results in less severe disease.

Other Names for This Gene

• BCD541
• C-BCD541
• centromeric SMN
• SMN_HUMAN
• SMNC

Genomic Location

Spinal muscular atrophy 1 (SMA1) is inherited in an autosomal recessive manner. This means that to be affected, a person must have a change (mutation) in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers are typically unaffected and do not have any signs or symptoms of the condition.

When two carriers of an autosomal recessive condition have children, each child has a:

• 25% chance to have the condition
• 50% chance to be an unaffected carrier like each of the parents
• 25% chance to not have the condition and not be a carrier.

An unaffected sibling of a person with SMA1 has a 2/3 chance to be a carrier.

Approximately 2% of cases of SMA1 are not inherited from both parents. In these cases, the affected person inherits one mutated copy of the gene from one carrier parent, and has a new mutation that occurs for the first time in the other copy of the gene.

Genetic testing for spinal muscular atrophy 1 (SMA1) is available. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible, if the disease-causing mutations in the family have been identified. SMA1 is caused by mutations in the SMN1 gene, and extra copies of the SMN2 gene affect the severity of the condition.

In some cases, interpreting results of carrier testing for SMA is difficult. Approximately 6% of parents of a child with SMA due to deletions in each copy of the gene have normal results of SMN1 dosage testing (carrier testing) for one of two reasons. Most people have one copy of SMN1 on each chromosome. However, about 4% of carriers have two copies of SMN1 on a single chromosome and a deletion on the other chromosome. These carriers with two copies of SMN1 on one chromosome are misdiagnosed as non-carriers by the SMN1 dosage test (they have a false negative test result). The second reason is that a new (de novo) deletion on one copy of the SMN1 gene occurs in 2% of people with SMA; in these cases, only one parent is a carrier.

The genetics of SMA1 is complex. People with specific questions about genetic risks and genetic testing for themselves or family members should speak with a genetics professional.

What is SMA?

Spinal Muscular Atrophy (SMA) is a genetic disorder that affects approximately 1 out of every 10,000 people. Most cases of SMA occur when a segment of a gene called SMN1 is missing, resulting in the gene being unable to make protein. SMN1 is primarily responsible for making survival motor neuron (SMN) protein, which is required for maintaining normal, motor neuron function. Without enough SMN protein, motor neurons will degenerate, causing progressive loss of controlled muscle movement. There are different levels of SMA severity. Typically, the earlier the onset of the disease, the more severe the symptoms. SMA can affect a baby’s ability to swallow, breathe, sit, and walk. Without early treatment, SMA can also result in premature death.

How do newborn screening programs detect SMA?

In routine newborn screening, state public health laboratories use dried blood spots collected from a baby’s heel within the first 24-48 hours of birth to detect genetic disorders including SMA.

To detect SMA, laboratorians perform a test to determine if the gene segment that causes SMA is missing. If the SMN1 gene is found to be abnormal, either the public health laboratory or a clinical laboratory will do further studies to identify the number of copies of the SMN2 gene. SMN2 also produces SMN protein but in smaller quantities that will not compensate for the amount missing due to the abnormal SMN1. As a result, when a baby has more than three copies of SMN2, SMA will likely develop later in life and typically in a milder form.

Treatment for SMA may vary depending on the subtype of SMA and severity of symptoms, but generally focuses on supportive care to increase the person's quality of life. In general, treatment may include physical therapy and assistive equipment to increase mobility, such as leg braces, walkers, and wheelchairs. Back braces may be used to assist sitting and prevent scoliosis and other complications affecting the backbone. Special breathing exercises, cough machines, and chest physiotherapy can help maintain the function of the lungs and keep the airways clear of mucous, especially in times of illness. A dietitian may help support nutrition if eating or swallowing becomes difficult.

For SMA types 1, 2, 3, and 4, nusinersen (Spinraza) is the first and only FDA approved treatment. Continued treatment with nusinersen has been found to increase motor function and slow the progression of symptoms. Many babies and young children with types 1 and 2 are able to reach developmental milestones and maintain those milestones over time. In general, breathing problems, nutrition problems, and hospital admissions also decrease. Older children with type 3 and adults with type 4 have also been shown to benefit from continuous treatment with nusinersen, including, for some, regaining the ability to walk longer distances, improving arm movement, and slowing or stopping the progression of the disorder. Ongoing, long term medical studies continue to report improvements. However, response to treatment does vary and some people with SMA types 1, 2, 3, or 4 may not respond to the drug at all or may have medical complications that prevent use of the treatment.