Scientists are closer to finding additional genetic causes for
the rare developmental disorder Cornelia de Lange Syndrome after
discovering the steps in brain development that may be affected in
some patients.
The findings come from a team at the Francis Crick Institute who
worked with colleagues at the Proteomics Centre at Erasmus
University Medical Centre in The Netherlands.
Debbie van den Berg, who is in François Guillemot's group at the
Crick, explains: "Cornelia de Lange Syndrome affects the central
nervous system. Patients experience seizures and various degrees of
intellectual disability.
"For seven in every 10 patients the altered genes that cause the
syndrome are known, but it is not understood how these alterations
influence brain development. For the other three in 10 patients,
the genetic cause is unknown."
Researchers have previously found that over half of patients
with Cornelia de Lange Syndrome have mutations in one of two copies
of a gene called cohesin loading factor Nipped-B-like (NIPBL).
These patients tend to be more severely affected than those without
a mutation in this gene. However, how NIPBL acts in gene regulatory
networks and developmental pathways in brain development was poorly
understood.
The researchers discovered in mice that the Nipbl protein binds
to two other protein factors, called Zfp609 and the Integrator
complex. They found that, together, these three factors regulate
how nerve cells travel from their site of origin to their final
destination in the developing brain.
When the scientists disabled Nipbl, Zfp609 or Integrator in
mouse brains, their nerve cells failed to reach the correct
positions. This affected the building and wiring of their brains,
which can result in the neurological problems seen in patients with
Cornelia de Lange Syndrome.
Dr van den Berg says: "We now have a better understanding of
which steps in brain development are affected in this disease. Our
data have provided new clinical insights and have contributed
candidate genes for mutation screening in this and other
intellectual disability syndromes."
Dr Guillemot adds: "By screening for mutations in the genes for
these additional regulator proteins - Zfp609 and the Integrator
complex - we might be able to find a genetic cause for Cornelia de
Lange Syndrome in patients for whom no cause has been found so
far."
The paper, Nipbl interacts with Zfp609 and the Integrator
complex to regulate cortical neuron migration, is published inNeuron.