Understanding the disease

Spinal muscular atrophy (SMA) is an inherited neuromuscular disease, caused by deletion and/or mutation in the SMN1 gene (survival motor neuron). This gene is responsible for the production of a protein which is essential to the proper working of the motor neurons. People who are missing both copies of SMN1 have SMA, while carriers are missing only one copy.

There is a similar copy of SMN1, called SMN2, which even people with SMA always have. However, the SMN2 gene is just different enough that it does not 'quite' produce the necessary protein. The lack of this protein causes the motor neurons in the spinal cord to degenerate - resulting in SMA. It isn't possible to simply inject this protein into the bloodstream or muscles, or eat it - it is produced within individual cells for use within those cells. However, if the SMN2 gene could somehow be changed, so that it produces the correct protein, in sufficient quantity, this might lead to an effective therapy for SMA.

To see how this might be done, we need to understand a little about the structure of genes and how they make proteins. Normally, a gene is composed of exons (the important parts of the gene, that also encode the protein) and introns (the nonsense, filler portion, which is cut out in the process of splicing). The DNA (which includes introns and exons) is transcribed into RNA, which in the first stage contains the same exon-intron structure as the DNA. In a second stage the introns are spliced (cut out) and the exons are attached to each other forming the mature RNA (mRNA). The mRNA encodes the protein. These proteins build, support, and maintain individual cells. There are millions of different proteins, each serving a special purpose in various types of cells.

So, how is SMN2 similar to SMN1, and how is it different?
The SMN gene encompasses 9 exons (1, 2a, 2b, 3, 4, 5, 6, 7, 8). While the SMN1 mRNA usually contains all 9 exons (full-length SMN1), SMN2 mainly produces mRNA that lacks exon 7 (SMN2D7) and thus the SMN2 protein is truncated (shortened). But exactly exon 7 encodes a very essential part of the protein that gives SMN the capacity to oligomerize (bind) with itself. In order to function correctly, the SMN monomers (single copy of the protein) have to ligate to each other to form oligomers (multiple copies of the protein).
Phrased simplistically, we can say: SMN2 is missing a very important part - a certain exon - which allows the resulting proteins to attach themselves to each other in order to work properly.

Ten years ago a researcher identified the reason that causes the different splicing of SMN1 and SMN2. Normally, a complex mechanism within the cell understands how to make RNA from DNA, retaining the meaningful portions and cutting out the nonsense portions for the RNA. However, because of a single mistake (a nucleotide exchange) in exon 7, that machinery doesn't work perfectly, and SMN2 produces only about 30% of the protein correctly. However, this 30% is identical to the protein which would normally be made by the missing SMN1 gene.

People with SMA have no copies of SMN1 but they still have SMN2. This means that in SMA patients the production of good SMN protein is far less than in unaffected individuals - but they have some of it. This is enough for the correct function of most of the cells in the human body, but not for the motor neurons in the spinal cord, which degenerate - leading to atrophy and weakness of the voluntary muscles. There is also a clear correlation between the number of SMN2 copies and the severity of SMA. The more copies an SMA patient carries, the milder is the phenotype - the less severely that person is affected (this is why, when Dr. Arthur Burghes engineered mice which had no SMN1 genes and 8 SMN2 genes, the mice were not affected with SMA).


(sources: FSMA, AFM and UILDM websites)