Brain deformities previously thought unrelated can now be traced back to mutations in a single gene critical for the development of the human cerebral cortex, report Yale researchers in the August 22 edition of the journal Nature.
The findings show how one gene is responsible for regulating the production of cortical neurons, maintaining the journey of these neurons to critical sites within the brain, developing the distinct folding of human brain tissue in the cortex and even delegating the size of the brain itself.
“Mechanistically, we know little about how the human cerebral cortex develops and the genes involved in this process. Cutting-edge molecular genetic approaches now allow us to dissect this complex process. Understanding the normal function of molecules like WDR62 will get us a step closer to solving this amazing puzzle,” said Murat Gunel, senior author of the paper and Nixdorff-German Professor of Neurosurgery, Genetics and Neurobiology at Yale.
During a long-term partnership between Gunel and Turkish scientists, the Yale team carefully observed two cousins from Turkey born with especially underdeveloped cerebral cortices causing considerably smaller-than-average brains.
The researchers found that both cousins displayed signs of abnormalities in the movement of cortical neurons to their normal destinations as well as defects in the usual cortex foldings. These deformities were previously thought to be completely separate problems, but finding these similarities in two related subjects suggested there might be a single underlying cause, noted the researchers.
To further test this theory, the scientists used whole exome sequencing, a technology created at Yale that allows the rapid and relatively inexpensive sequencing of all the protein coding genes in the human genome. The investigators then pinpointed mutations in both copies of the gene encoding the protein WDR62.
When the researchers sequenced this same gene in other patients with deformities in cerebral cortical development, they were able to identify six additional families with mutations in both copies of WDR62.
“Because patients with mutations in this gene were only a fraction of the total cohort, this gene would have been very difficult to map and identify using traditional genetic approaches,” said Richard Lifton, Sterling Professor and Chair of Genetics at Yale, whose lab developed the exome sequencing and analysis techniques used in this study.
The results offer startling insights into the many roles that a single gene can play in brain development, noted the scientists.
“The study of disorders of the human brain is undergoing a revolution as a result of new sequencing technologies,” said Matthew W. State, the Donald J. Cohen Associate Professor of Child Psychiatry, Psychiatry and Genetics, who designed the study along with Gunel and Lifton. “The approaches used in this study promise to unlock many of the mysteries regarding the genetics of developmental disorders ranging from cortical malformations to autism to mental retardation,” he added.
Ali Ozturk and Kaya Bilguvar from Yale are the co-first authors of the study. Several other researchers from Yale contributed to the study, as well as several Turkish clinicians and scientists. Major funding for the study was provided by a stimulus grant from the National Institutes of Health, National Institute for Neurological Disorders and Stroke.
“The ongoing collaboration with our Turkish colleagues along with the technology development at Yale combined with the timely NIH funding allowed us to achieve these results,” said Gunel. “It would not have been possible without the stimulus funding,” he said, also adding that additional funding was provided by the Howard Hughes Medical Institute and Yale University.
Source: Yale University