Neurodevelopmental disorders (NDDs) like schizophrenia, autism and
bipolar disorders encompass a wide range of disabilities associated with
the functioning of the brain. Severe NDDs are currently known to affect
approximately 5% of the population, making understanding their causes
and in turn, their possible treatments an important area of study.
The human genome is made up of approximately three billion letters of DNA and at each
position it is possible to have different letters, called variants. Some
variants are harmless but others can be detrimental, making it a
mammoth task to find out which variants cause a disorder.
‘Defect in non-coding DNA might trigger brain disorders such as severe language impairment.’
often choose to search only the 1-2% of the genome that carries the
information to make proteins. While this has been successful for a few
disorders, most neurodevelopmental disorders are still largely
unexplained, making it clear that looking elsewhere in the genome is
"The remaining 98% of the genome offers a lot of untapped potential
to find changes that can cause disorders" Paolo Devanna, co-author of
the study explains. "These parts of the genome are known as
'non-coding', but that doesn't mean that they are not important. They
have very vital jobs to do, for example to control when, where and how
much protein is made. So if this process gets messed up, it could have
severe consequences, like neurodevelopmental disorders." For this
reason, Devanna and his colleagues decided to look at the so called
3'UTRome. This is a part of the non-coding genome that regulates how
much protein is made.
Searching for causes of language impairmen
To test this approach, the researchers looked at the DNA of children
with severe language problems and identified genetic variants in the
3'UTRome. "Language disorders are a very complex neurodevelopmental
disorder and finding their genetic causes has been particularly
challenging - we have only a small number of candidate genes thus far"
said Dr. Sonja Vernes who led the study. She runs a research group at
the Max Planck Institute for Psycholinguistics and is part of the
Donders Institute for Brain, Cognition and Behavior at the Radboud
University, both in Nijmegen, the Netherlands.
The researchers tested the impact of each 3'UTRome variant on the
expression of the candidate genes for languages impairment. One of the
variants has a significant effect on the expression of a gene known as
ARHGEF39. "If a cell carries this single letter change in the 3'UTRome,
they express more ARHGEF39. We were very excited by this finding because
this is the first time we have found a variant associated with specific
language impairment that we can show has a clear biological effect,"
said Devanna. "Having too much of a protein at important points in
development could affect how neurons and neuronal circuits develop and
function, which could in turn could affect how children develop their
language skills" Vernes explains.
Non-coding variants are widespread in genetic disorders
Given this success, the researchers went on to explore the 3'UTRome
in other neurodevelopmental disorders. They identified 25 further
genetic changes in the DNA of individuals with autism, schizophrenia and
bipolar disorder that are thought to control protein levels in the same
way. "We are tapping into a new and promising source of genetic
variation" Vernes said. "Our study shows that the identification and
testing of non-coding variants will foster our understanding of the
genetic causes of neurodevelopmental disorders, which is crucial in the
long term for the design of new and effective therapeutics."