NEW YORK (GenomeWeb) – Two new studies have linked mutations in the DCC gene to brain malformations affecting children with developmental disabilities.
DCC, which encodes an axon-guidance receptor, has been previously linked to congenital mirror movements (CMMs) in which intentional movements made on one side of the body are mirrored unintentionally on the other side.
One paper appearing today in Nature Genetics has now also linked truncating and missense mutations in DCC to lacking all or part of the corpus callosum brain region that mediates communication between the two brain hemispheres, while a second Nature Genetics paper described a new genetic syndrome attributable to biallelic DCC mutations that is marked by horizontal gaze palsy, scoliosis, and intellectual disability.
In the first paper, researchers led by Christel Depienne at the Hôpital de la Pitié-Salpêtrière in Paris conducted linkage analysis and exome sequencing on individuals from three families with agenesis of the corpus callosum (ACC), CMMs, or both, and direct screening of the DCC gene in a fourth affected family.
In each of the families, the researchers uncovered variants — both truncating and missense variants — within DCC that segregated with disease that were absent from public variant databases. Further, in a cohort of 70 unrelated individuals with AAC, the researchers uncovered five people with missense DCC variants.
Depienne and her colleagues estimated the penetrance of CMM and ACC to be 42 percent and 26 percent, respectively, though they noticed differences in frequency between males and females: CMMs is more common in males and ACC in females.
In human neural stem cells, the researchers found that there was a dose-dependent effect of testosterone on DCC expression. This suggested to them that ACC could occur when DCC mRNA and protein levels falls below a certain threshold, which would be more likely to occur in females. They noted that other genetic, epigenetic, and environmental factors could also affect the phenotype.
Missense DCC mutations commonly affected the Netrin-1-binding domain, though at various sites, they added, could also contribute to differing disease presentations. Netrin and DCC are both key components of an axon guidance signaling pathway that is evolutionarily conserved in vertebrates and Caenorhabditis elegans.
"[O]ur results provide compelling evidence that DCC mutations cause isolated ACC in humans, in addition to the previously reported [CMM] phenotype," Depienne and her colleagues wrote in their paper.
Meanwhile, Boston Children Hospital's Timothy Yu and his colleagues investigated the genetic source of a syndrome that appears to combine aspects of ACC and horizontal gaze palsy with progressive scoliosis (HGPPS). Homozygosity mapping of affected members in one family homed in on a seven kilobase homozygous deletion affecting exon 1 of DCC that was confirmed by digital droplet PCR. In another family, meanwhile, targeted sequencing uncovered a seven basepair deletion in DCC in exon 4. Both variants were absent from public databases.
"[T]his is, to our knowledge, the first report of human biallelic mutations in DCC in association with a new genetic syndrome of horizontal gaze palsy, scoliosis, ACC, and midline brainstem cleft," Yu and his colleagues wrote.
The researchers noted that the overlap of the human DCC-knockout phenotype with HGPPS might be important mechanistically. HGPPS has been linked to biallelic mutations in ROBO3, which the researchers noted encodes an axon guidance receptor that interacts with DCC to enhance Netrin binding. This suggested to them that there could be other candidate disease genes in the Netrin-DCC pathway.
Yu and his colleagues also suggested that patients presenting with horizontal gaze palsy, scoliosis, ACC, and midline brainstem malformations should be screening for DCC mutations. Depienne and her colleagues noted in their own paper that the frequency of DCC mutations uncovered in their cohorts suggests that it could have implications for prenatal diagnostic and counseling efforts.