The presence of two copies of the Survival Motor Neuron 1 (SMN1) gene is a central topic in the context of genetic health, particularly concerning the neuromuscular disorder Spinal Muscular Atrophy (SMA). Genes provide the blueprint for the body’s proteins, and humans typically inherit one copy of each gene from each parent. The SMN1 gene is responsible for producing a protein that is necessary for the maintenance and function of specialized nerve cells called motor neurons. Genetic testing often focuses on this gene to determine an individual’s risk for being a carrier of SMA or for developing the condition itself.
The SMN1 Gene and Its Essential Function
The SMN1 gene gives the body instructions to create the Survival Motor Neuron (SMN) protein, which is found throughout the body but is concentrated in the spinal cord’s motor neurons. Motor neurons are the long, specialized nerve cells that relay signals from the brain and spinal cord to the skeletal muscles, controlling voluntary movement like walking and breathing. The SMN protein is a component of a larger assembly called the SMN complex, which plays a role in processing messenger RNA (mRNA). Without sufficient levels of the SMN protein, motor neurons cannot maintain their health and integrity, leading to their progressive loss. The death of these nerve cells results in the muscle weakness and wasting that characterizes Spinal Muscular Atrophy. In over 90% of SMA cases, the condition is caused by a deletion or mutation in both copies of the SMN1 gene.
The Significance of Having Two SMN1 Copies
For most individuals, having two copies of the SMN1 gene, one inherited from each biological parent, signifies a standard, healthy genetic status concerning SMA. This is the expected number of functional copies in an unaffected person, and it means they are producing a sufficient amount of the full-length SMN protein to maintain motor neuron function. An individual with two intact SMN1 copies is not at risk of developing Spinal Muscular Atrophy.
The inheritance pattern for the common forms of SMA is autosomal recessive, meaning the disease only manifests if a person inherits two non-working copies of the SMN1 gene. Therefore, a person with two working copies cannot pass on a non-working gene from that chromosome, significantly reducing the risk of having a child with SMA.
However, a subtle complexity exists in carrier screening because some individuals have two copies of the SMN1 gene located on the same chromosome, with zero copies on the other chromosome, an arrangement sometimes called a “2+0” genotype. This unusual arrangement can lead to a person being a “silent carrier” because standard genetic tests might count two total copies and incorrectly conclude they are not carriers. Specialized testing can help clarify this status, particularly for individuals with a family history of SMA or for reproductive partners of known carriers.
The SMN2 Gene
In addition to the SMN1 gene, humans also possess a nearly identical gene called SMN2. The two genes are located close together on chromosome 5 and are structurally highly similar. A single nucleotide difference in SMN2 causes the gene to be “mis-spliced,” leading to the exclusion of exon 7 in most of the resulting mRNA. The exclusion of exon 7 results in a truncated, unstable, and largely non-functional SMN protein.
The SMN2 gene still produces a small amount—typically 10% to 15%—of the full-length, functional SMN protein. This small percentage is the primary determinant of SMA severity. The number of copies of the SMN2 gene varies significantly between individuals, generally ranging from one to eight copies. People with SMA, who have zero functional SMN1 copies, rely entirely on their SMN2 copies. A higher SMN2 copy number means a greater total output of functional SMN protein, which correlates with a milder disease course. For example, individuals with the most severe form of SMA typically have one or two SMN2 copies, while those with milder, adult-onset forms may have four or more copies.
Spinal Muscular Atrophy: Types, Symptoms, and Modern Treatment
The clinical presentation of Spinal Muscular Atrophy is highly variable and has traditionally been categorized into types (0 to 4) based on the age of onset and the highest motor milestone achieved, which broadly aligns with the patient’s SMN2 copy number. Type 1 SMA, the most common and severe form, manifests at or near birth, with infants experiencing severe muscle weakness, inability to sit independently, and severe breathing and swallowing difficulties.
Type 2 SMA, with onset between 6 and 18 months, allows children to sit but generally prevents them from walking. Type 3 presents after 18 months, with individuals initially achieving the ability to walk before experiencing mobility decline later in life.
The prognosis for SMA has been transformed by modern therapeutic interventions that directly target the underlying genetic deficiency.
Antisense Oligonucleotide Treatment
One approach uses antisense oligonucleotide treatment, such as nusinersen (Spinraza). Delivered via spinal injection, it works by modifying the splicing of the SMN2 gene to increase the production of full-length, functional SMN protein. Another oral medication, risdiplam (Evrysdi), also acts as an SMN2 splicing modifier and has been approved for a wide range of patients.
Gene Therapy
The development of gene therapy, exemplified by onasemnogene abeparvovec (Zolgensma), is a single-dose intravenous treatment approved for young children. This therapy uses a modified virus to deliver a functional copy of the SMN1 gene directly to the motor neuron cells.
These treatments, especially when administered pre-symptomatically through newborn screening, can halt or significantly slow the progression of the disease, allowing many children to reach motor milestones previously unimaginable for their SMA type.