Beyond finding a gene

23 July 2019

Families living with rare neurodegenerative diseases finally received an answer to the cause of their illnesses, as a result of a researcher's hunch and decades of improvements in DNA sequencing technology.

Four different rare diseases are all caused by the same short segment of DNA repeated too many times, termed noncoding expanded tandem repeats. Researchers suspect variations of this type of mutation may cause other diseases that have thus far evaded diagnosis by genetic testing.

“Because the mutations causing the diseases are so similar, in the future, all these patients might benefit from the same treatment,” explained Hiroyuki Ishiura, assistant professor from the University of Tokyo Hospital and first author of paper published in Nature Genetics.

The research team focused on patients with adult-onset neurodegeneration, showing symptoms like cognitive impairment, uncontrolled movement, loss of balance, weakness in the arms and legs, or difficulty swallowing. The genetic cause of one disease with those symptoms, fragile X tremor/ataxia syndrome, was identified in the early 2000s as three letters of the genetic code, CGG, being repeated dozens or hundreds of times on the X chromosome. Noncoding expanded tandem repeat mutations can be caused by any letters of the genetic code repeated an unusual number of times anywhere in the genome.

Researchers had a hunch that the same CGG repeat mutation might cause three other rare diseases with similar symptoms and clinical test results. But since patients with those other diseases had normal X chromosomes, researchers had no idea where in the genome the potential CGG repeat mutations might exist.

The team hope that their studies on rare neurodegenerative diseases might lead to insights into more common diseases caused by other types of noncoding tandem repeat mutations, including amyotrophic lateral sclerosis (ALS), also known as motor neuron disease or Lou Gehrig's disease.



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