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Doubling Shank3 corresponds with mania seen in bipolar patients

Two chromosomes show duplications in genetic material between vertical lines. These areas contain the SHANK3 genes. Image courtesy the journal Nature.

When the gene SHANK3 is mutated or missing, it plays a central role in some forms of autism, including Phelan-McDermid syndrome. It’s been difficult to figure out if duplications of the gene have a detrimental effect, however, because duplications in humans usually involve a large region of the chromosome that includes genes besides SHANK3. Now a team led by scientists at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital have found that when the gene is duplicated in mice, the animals exhibit a kind of hyperactivity that seems to correspond with a type of mania sometimes seen in bipolar patients.       

“We have also found a couple of patients who had similar duplications of SHANK3. One had been diagnosed as having bipolar disorder and the other was believed to have ADHD (attention-deficit hyperactivity disorder) that did not respond well to typical treatment,” said Dr. Huda Zoghbi, professor of molecular and human genetics at BCM, director of the NRI and corresponding author of the report that appears in the journal Nature.

“There was previously no strong evidence that the duplication of SHANK3 had an effect,” said Dr. Kihoon Han, a postdoctoral fellow at BCM and a first author of the report. “But by generating a mouse that had a small duplication of just the SHANK3 gene, we can now say that not just too little but also too much expression of this gene influences brain function.”

Dr. J. Lloyd Holder, Jr., a co-author and assistant professor of pediatrics – neurology at BCM, recently saw another patient with this problem in the clinic at Texas Children’s Hospital.

“This work provides an explanation for those patients whose hyperactivity or mania do not respond to the usual drugs. We’ve suspected that there might be some underlying genetic difference, but now we have something we can test for that could lead to improvement in patient care,” he said.

In the mice with the duplication, drugs usually used to treat ADHD do not work. The symptoms improved, however, with a drug called valproate, which is sometimes used in bipolar disorder patients who do not respond to lithium.

Zoghbi and her colleagues began their research with the intention of determining which proteins interacted with the protein Shank3 (encoded by the gene SHANK3) at the synapse, that critical junction at which information is passed from one nerve cell to the next.  

That is why they created the mouse with the duplication of the SHANK3 gene. They were not sure how that would affect the mice, but Zoghbi was in the animal room one day when she heard a commotion coming from the corner.  

“I asked, ‘Who is making that ruckus?’ It was the SHANK3 duplication mouse, running like mad around its cage. That was the clue that the extra copy of the SHANK3 gene was doing something,” she said.

They decided to look more closely at the brains of the mice to understand what was causing the effect. They found that the neurons in these mice were hyper-stimulated. Using a bioinformatic approach to create an ‘interactome’ of all the proteins that interact with one particular protein of interest, the scientists found that SHANK3 interacts with the Arp2/3 complex to increase levels of a form of a critical protein called F-actin.

“SHANK3 interacts with proteins at the synapse that are important to creating extra excitatory synapse spines that are important for transmitting messages between neurons. When there are too many of these, it leads to hyperexcitabiity and mania,” said Zoghbi.

“There are patients with ADHD or mania that respond to some classes of drugs and not others,” said Holder. “Most of the time, we don’t figure out why. As we go forward, figuring out specific genetic causes could lead to a more specific treatment.”

“This all started with a curiosity about the proteins at the synapse that interact with Shank3,” said Zoghbi. “We ended up with information that might help human patients and find a genetic cause—and treatment— for a subset of them.”

Others who took part in this work include: Christian P. Schaaf, Hui Lu, Hongmei Chen, Hyojin Kang, Jianrong Tang, Zhenyu Wu, Shuang Hao andPeng Yu, all of the BCM and the NRI; and Sau Wai Cheung, Amy M. Breman and Ankita Patel of BCM and the Medical Genetics Laboratories at BCM; and Hui-Chen Lu and Hao Sun of the Cain Foundation Laboratories and BCM. Kang is now with the National Institute of Supercomputing and Networking, Korea Institute of Science and Technology Information, Daejeon, Korea.

Funding for this work came from The Howard Hughes Medical Institute, a National Institutes of Health (NIH) ARRA grant (1R01NS070302), the Baylor Intellectual and Developmental Disabilities Research Center (P30HD024064), confocal, electrophysiology and mouse neurobehavioral cores, the Cancer Prevention and Research Institute of Texas (CPRIT) RP110784, the Thrasher Research Fund, the NIH (Grant 2T32NS043124) the Ting Tsung and Wei Fong Chao Foundation, the Joan and Stanford Alexander family, and the Doris Duke Clinical Scientist Development Award.