Mutations in a single gene critical to the development of the human cerebral cortex can cause a host of brain deformities previously thought to be unrelated, Yale researchers report online August 22 in the journal Nature.
The surprising findings describe how a single gene can regulate the production of cortical neurons, their migration to proper sites within the brain, the folding of brain tissue that marks the human cortex and even the size of the human brain compared to its primate cousins.
“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, the Nixdorff-German Professor of Neurosurgery, Genetics and Neurobiology at Yale and senior author of the paper.
As part of a long-term collaboration between Gunel and Turkish scientists, the Yale team studied two cousins from Turkey born with extremely underdeveloped cerebral cortices resulting in significantly smaller brains. The cousins also showed evidence of an abnormality in the migration of cortical neurons to their normal destinations and abnormalities in the normal folding of the cortex. These deformities were previously believed to be separate disorders, but finding all these features in two related subjects suggested there might be a single underlying cause, noted the researchers.
To test this theory, the investigators used whole exome sequencing, a technology pioneered at Yale that enables the rapid and relatively inexpensive sequencing of all the protein coding genes in the human genome. The investigators identified mutations in both copies of the gene encoding the protein WDR62. Upon sequencing this gene in additional subjects with malformations of cerebral cortical development, the scientists identified 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 methods used for this study.
The results offer surprising insights into the diverse 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.
Kaya Bilguvar and Ali Ozturk from Yale are the co-first authors of the study. A dozen other researchers from Yale contributed to the study, as did 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 added, noting that additional funding was provided by Yale University and the Howard Hughes Medical Institute.