Progressive diseases are among the most dreaded kind, because they worsen over time. And, as the disease goes from one generation to the next, the severity increases and the age of onset decreases. Researchers are aware of some 40 neurological, neurodegenerative, and neuromuscular diseases that share a common element – they contain mutations in the form of repeating DNA that grows longer through the life of a patient, making the condition worsen.
In an international study, scientists from The Hospital for Sick Children (SickKids), along with a research team in Paris, France, uncover the workings behind this dynamic mutation.
Progressive diseases include Huntington’s disease and myotonic dystrophy (a form of muscular dystrophy) and fragile X syndrome (most common cause of inherited mental impairment). The SickKids team looked specifically at myotonic dystrophy, which is a multisystem disorder that affects skeletal and smooth muscle as well as the heart, endocrine system, and central nervous system. They found that the mutation is caused by a slippage of the DNA as it replicates. They also identified the location on the DNA where this slippage starts and which tissues are affected at various ages.
Dr. Christopher E. Pearson, principal investigator of the study, Senior Scientist at SickKids and Associate Professor in the Department of Molecular Genetics at the University of Toronto, explains the concept behind repeat mutations:
“Consider the gene as a sentence that reads, ‘THE CAT ATE THE FAT FAT RAT’. In repeat-associated diseases, the mutation would be ‘THE CAT ATE THE FAT FAT FAT FAT FAT FAT FAT RAT’. These repeated DNAs are slippery,” says Pearson.
Myotonic dystrophy type 1 affects 1 in 8,000 worldwide, and is up to 60 times more prevalent in Quebec than elsewhere in the world.
“We are moving towards being able to treat progressive diseases by arresting or reversing the repeat mutation. In other words, we hope to be able to prevent, or even better, reduce the expansion of the number of ‘FAT’ units,’ says Pearson. “Knowing when, where, and how this mutation occurs, helps us determine when and where to treat as well as what to target.”
In theory, the clinical benefit of stopping or reversing these expansions would be to reduce or reverse the progression of the disease. Over the next 10 years, the SickKids team hopes to identify compounds that can modify the mutation by inhibiting it or reversing it.
As a geneticist, Pearson’s lab will be relocated to the Genetics & Genomics in Child Health neighborhood in the new SickKids Research & Learning Tower. This will encourage interactions with colleagues from other scientific disciplines to improve our understanding of diseases such as Huntington’s disease, myotonic dystrophy, fragile X syndrome, and spinal cerebella ataxias.
Illustration: The Hospital for Sick Children.
SickKids News Release (08/15/10)
Abstract (Nature Structural & Molecular Biology; 17, 1079-1087 (08/15/10))