Scientists have uncovered a variant (mutation) in the SMN2 gene that leads to production of more full-length SMN protein molecules and a milder version of spinal muscular atrophy (SMA). The finding, a naturally occurring point mutation (a single letter change in the DNA code) in this gene, has immediate implications for genetic testing and possible long-term implications for therapy development.
The new SMN2 gene variant was uncovered by scientists at Ohio State University in Columbus, Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y., and the University of Utah School of Medicine in Salt Lake City, who published their results online August 27, 2009, in the American Journal of Human Genetics.
SMA causes a loss of muscle-controlling nerve cells (motor neurons) in the spinal cord and results in profound weakness or paralysis of voluntary muscles.
In its most severe form, known as type 1 SMA, the disease affects infants, causing impairment of the breathing and swallowing muscles. Types 2, 3 and 4 SMA affect children and adults, causing varying degrees of loss of strength and mobility.
The molecular cause of the disease is a deficiency of a protein called SMN, which stands for "survival of motor neurons." The gene from which this protein is made is located on chromosome 5 and is known as SMN1.
The SMN1 gene is missing in people with SMA. However, one or more copies of a second gene, called SMN2, are located on chromosome 5 and a small amount of functional SMN protein can be made from this gene. Usually, but not always, the more copies of SMN2 a person has, the better he or she is able to compensate for the loss of the SMN1 gene.
When the SMN1 gene is missing, disease severity can be estimated by counting the number of SMN2 genes. However, the correlation isn't perfect, suggesting there are modifiers of disease course in addition to gene copy numbers.
About the new findings
Normally, SMN2 genes contain a code that allows cells to omit a section known as "exon 7" from the final genetic instructions used in making proteins. The newly identified variant in the SMN2 gene causes exon 7 to be included in the final instructions, resulting in the synthesis of more full-length, fully functional SMN protein.
In three SMA patients with mild forms of the disease, initial testing revealed fewer copies of the SMN2 gene than would have been expected. (Their relatively mild disease course usually correlates with greater numbers of SMN2 genes.) Enhanced testing in each of the three revealed previously undetected copies of the SMN2 gene, each of which contained the same point mutation.
The investigators also screened 41 patients with severe (type 1) SMA, and found that none had the mutation.
Several former and current MDA grantees formed the bulk of the research team that characterized the variant SMN2 gene.
"MDA has been very, very generous to all of the authors on this paper over the years," said lead author Thomas Prior, who directs the Molecular Pathology Laboratory at Ohio State University. Prior has received MDA funding in the past for related work.
Arthur Burghes, also from Ohio State, Adrian Krainer from the Cold Spring Harbor Laboratory and Kathryn Swoboda from the University of Utah, all have current MDA grants for related work in SMA. MDA grantee John Kissel is co-director of the MDA clinic at Ohio State University Hospital.
Meaning for patients
There are two major clinical applications related to the finding, Prior noted.
First, he said, discrepant cases, in which a patient's SMN gene copy counts don't correlate with disease severity, "may be explained by our new modifier or other modifiers inside the SMN2 gene." As highlighted by the differences in SMN2 gene expression observed in the study, "it should not be assumed that all SMN2 genes are equivalent."
If genetic testing could be developed to detect this particular variant or others that may be found, it would allow for a more accurate prediction of the disease course.
Second, it's possible that the variant provides a possible lead for future therapies. The cases presented in the study, Prior explained, support the possibility of "a potential therapeutic benefit in increasing SMN2 gene expression" to decrease the severity of the disorder.