These findings could be the first step toward the identification of new SMA modifiers.
The study, “DYNC1H1 gene methylation correlates with severity of spinal muscular atrophy,” was published in Annals of Human Genetics.
Spinal muscular atrophy (SMA) is a genetic neurodegenerative disorder characterized by the gradual loss of motor neurons — the nerve cells responsible for controlling voluntary muscles — in the spinal cord, leading to muscle weakness.
SMA is caused by mutations in the SMN1 gene, which encodes for the SMN protein that is essential for motor neurons’ survival. SMN2 — a gene similar to SMN1 that can provide tiny amounts of a full-length SMN protein — typically remains unaffected in SMA patients and, depending on the number of copies present, can modify the course of some forms of the disease (SMA modifier).
However, there are still cases of patients presenting the same type of SMN1 mutations and the same number of SMN2 copies that differ dramatically in terms of disease severity, suggesting other factors may be at play.
One such factor could be the presence of DNA modifications that change the way a gene is expressed, in particular methylation — a chemical modification in which the addition of small chemical groups (methyl) are able to “turn off” a gene, or prevent it from being expressed.
Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.
A previous large-scale study, performed by the same team of researchers, revealed the presence of distinct methylation patterns among patients with different levels of disease severity in genes involved in the development of SMA.
Now, researchers looked more closely at the association between three of these genes DYNC1H1, SLC23A2 and CDK2AP1, and SMA severity, using a technique called methylation-sensitive, high-resolution melting (MS-HRM), to analyze differences between methylated and unmethylated DNA sequences.
In particular, researchers looked at specific regions of the DYNC1H1 gene, namely exon 41 and 37. These regions were chosen according to the team’s earlier findings in whole-genome methylation studies. (An exon is a portion of a gene that provides instructions to make a protein.)
No significant differences were found in the methylation patterns of SLC23A2, CDK2AP1 and on exon 41 of the DYNC1H1 gene between the two groups of SMA patients.
However, on exon 37 of the DYNC1H1 gene, researchers found a significant decrease in DNA methylation among SMA patients with the most severe form of the disease (type 1) in comparison with those affected by milder SMA forms (types 3 and 4).
“According to our data, exon 37 of the DYNC1H1 gene is hypermethylated [excessively methylated] both in severe and mild forms of SMA, and milder SMA phenotype correlates with a completely methylated state (assessed as 99.9% of methylation level). Methylation difference in between both groups was estimated as 1.5%, (…) indicating that even a small deviation from the hypermethylated state of the gene have substantial outcomes,” researchers wrote.
Considered together these findings indicate that DNA modifications, in particular methylation, are distinct in different types of SMA and could be useful to identify new disease modifiers.
“The observed correlation is functionally plausible — decreased methylation of the body of the DYNC1H1 gene intimately involved in motor neuron functions correlates with a severe type of SMA — whereas its increased methylation is associated with milder phenotype,” the authors wrote.
“Furthermore, the results of the study support the application of MS-HRM technology for methylation studies as even small methylation differences could be detected by this method. Further studies of the DYNC1H1 gene can establish it as a putative SMA modifier,” they concluded.