A rare disorder called myotonic dystrophy type 1 (DM1) causes weakness and muscle loss that gets progressively worse. Patients with DM1 are about 14 times more likely to be diagnosed with autism spectrum disorder compared to the general population. Scientists have now found a connection between autism spectrum disorder (ASD) and DM1.
This work, which was reported in Nature Neuroscience, has shown that a genetic change that leads to DM1 also affects brain development. The genetic change that causes DM1 is known as a tandem repeat expansion (TRE), in which a portion of a gene is unusually long, and carries extra bases.
When genes are expressed, they are transcribed into RNA molecules, which are then modified in a variety of ways before being translated as proteins. One modification is known as splicing, in which parts of the sequence are removed and the rest is stitched together. TREs can disrupt gene splicing, leading to serious problems with the proteins that are then made from this mis-spliced RNA.
In DM1, the TRE occurs in a gene called DMPK, which is crucial to brain development. The TRE in the DMPK gene produces an RNA molecule that then disrupts the splicing of other genes. The aberrant, expanded DMPK RNA depletes a protein that regulates splicing, preventing it from attaching to other RNA molecules. The mis-splicing problem then affects many other molecules.
This may help explain why DM1 patients display social and behavioral traits associated with ASD. It could also indicate that genetic problems that lead to autism may not have to do with a loss of protein function; there may be other molecular causes.
"Our findings represent a new way to characterize the genetic development of autism," explained senior study author Dr. Ryan Yuen, a Senior Scientist at The Hospital for Sick Children (SickKids). "By identifying the molecular pathway behind this connection, we can begin to investigate new approaches to ASD diagnosis and the development of precision therapies that release these proteins back into the genome."
TREs are known to be related to ASD. Previous work has identified over 2,500 sites in the genome in which ASD patients are more likely to carry TREs compared to unaffected individuals.
"TREs are like a sponge that absorbs all these important proteins from the genome. Without this protein, other areas of the genome don't function properly," added Yuen.
TREs have also been implicated in other neurological disorders such as Huntington's disease.
Now, the researchers are hopeful that these findings with improve diagnostic and treatment options for DM1 patients and other individuals.