The Survival Motor Neuron 2 (SMN2) gene provides instructions for making the survival motor neuron (SMN) protein, found throughout the body, with highest levels in the spinal cord. This protein maintains specialized nerve cells called motor neurons, located in the spinal cord and brainstem. Motor neurons transmit signals from the brain and spinal cord to skeletal muscles, enabling movement. The number of SMN2 gene copies in an individual influences SMN protein production and is a key area in human genetics.
The Role of SMN1 and SMN2 Genes
The human genome contains two highly similar genes, SMN1 and SMN2, both encoding the survival motor neuron (SMN) protein. The SMN1 gene is the primary producer of full-length, functional SMN protein, essential for motor neuron health and function. In contrast, the SMN2 gene mainly produces a truncated, non-functional version of the SMN protein. This difference arises from a single nucleotide change, a C-to-T base change within exon 7 of the SMN2 gene.
This difference significantly alters the splicing pattern of the SMN2 gene’s messenger RNA (mRNA). While SMN1 primarily produces full-length functional protein, SMN2 mostly leads to exon 7 exclusion during splicing, resulting in an unstable, quickly degraded protein. However, 10% to 15% of the protein produced from SMN2 is full-length and functional. This small amount of functional protein from SMN2 can partially compensate for a lack of SMN1-produced protein.
What is a Typical SMN2 Copy Number?
The number of SMN2 gene copies varies among individuals. People typically have two copies of the SMN1 gene and one to two copies of the SMN2 gene, but SMN2 copies can range from zero to as many as eight. This variability in SMN2 copy number is a natural genetic characteristic and does not, on its own, indicate a health problem.
This variability highlights genetic diversity. Individuals can have different genetic makeups without adverse health effects.
SMN2 Copy Number and Spinal Muscular Atrophy
The number of SMN2 copies influences the severity of Spinal Muscular Atrophy (SMA), a genetic disorder primarily caused by mutations in the SMN1 gene. Patients with SMA have a homozygous deletion of the SMN1 gene, meaning they lack functional SMN1 protein. For these individuals, the SMN2 gene is the primary source of any functional SMN protein.
A higher SMN2 copy number correlates with a milder SMA phenotype because more SMN2 copies mean more functional SMN protein can be produced, partially compensating for the SMN1 deficiency. For instance, individuals with SMA Type 1, the most severe form, have one or two copies of SMN2 and experience severe muscle weakness early in life. Conversely, those with SMA Type 4, a milder, adult-onset form, have three to five copies of SMN2, and may not notice symptoms until adulthood. While a positive correlation exists between SMN2 copy number and disease severity, it is not an absolute predictor, and other genetic factors can also influence the clinical presentation.
How SMN2 Copy Number is Determined
Determining the SMN2 copy number requires genetic testing. This testing is performed for diagnostic purposes in individuals suspected of having SMA, or as part of carrier screening. Common laboratory methods used for this analysis include quantitative polymerase chain reaction (qPCR) and Multiplex Ligation-dependent Probe Amplification (MLPA).
MLPA is a widely used technique that quantifies nucleic acid sequences in a single reaction, effective for detecting SMN1 and SMN2 copy numbers. Quantitative PCR also accurately measures SMN1 and SMN2 copy numbers. While these methods are routinely used in clinical laboratories, they primarily detect the total copy number and may not identify certain complex genetic rearrangements.