A mutation associated with epilepsy and autism also is responsible for a “pale eye” trait in two rare genetic disorders, Angelman syndrome and Prader-Willi syndrome, neuroscientists at Vanderbilt University Medical Center reported this week.
Like many of the best stories in science, this discovery, which has implications for improving diagnosis and treatment of Angelman syndrome, began with the phrase, “That’s weird.”
It was a typical day in the lab of Jing-Qiong (Katty) Kang, M.D., Ph.D., when research assistant Kelienne Verdier noticed something unusual about a group of newborn mice. Most of the mice had small black eyes, but a few had eyes so light-colored that Verdier could hardly see them.
Kang, assistant professor of Neurology and a member of the Vanderbilt Kennedy Center for Research on Human Development, studies epilepsy, not the eye. Yet she was intrigued by Verdier’s observation.
With the help of Kelli Boyd, DVM, Ph.D., in the Translational Pathology Shared Resource Core, and Janice Williams, Ph.D., in the Cell Imaging Shared Resource, she analyzed tissue samples using electron microscopy and other techniques.
“We found there’s no melanin (pigment) at all in the eye,” Kang said.
To solve the mystery, Kang brought in postdoctoral fellows Ryan Delahanty, Ph.D., and Yanfeng Zhang, Ph.D., who were experts in analyzing DNA and RNA sequencing data, and Terry Jo Bichell, Ph.D., a Neuroscience graduate student whose son has Angelman syndrome, a rare genetic disorder with similarities to autism or cerebral palsy.
Bichell seized on the eye color observation. Many children with Angelman’s syndrome have pale eyes, and her son has lighter eyes than the rest of the family.
At the time, scientists believed the lighter eye trait in Angelman and Prader-Willi syndromes was a by-product of the deletion of a gene called OCA2, which is involved in melanin transport.
Kang wasn’t convinced. Several years earlier she and Delahanty had studied another gene, GABRB3, which is mutated in autism and epilepsy. After examining both genes, they discovered their hunch was correct. OCA2 structure was normal. Only the loss of GABRB3 affected the eye pigmentation.
Their paper, published this week in the journal Cell Reports, is the first description of a GABRB3 mutation with effects outside the brain. It also challenges current thinking about Angelman syndrome.
GABA is an excitatory neurotransmitter. The beta 3 subunit of the GABA receptor, GABRB3, is essential for receptor assembly and normal brain development. Mutations in the receptor are associated with epilepsy, autism and cognitive disabilities.
Angelman syndrome is not considered to be a developmental disorder, but rather “something that kicks in after birth,” Bichell said. That thinking may have to change, she added, because the GABRB3 mutation is correlated with a prenatal dysfunction in the pigment layer of the retina, which results in the lighter eye color.
Children with Angelman syndrome have one intact gene from their father, but are missing the gene from their mother.
“So they’re receiving a half dose of GABRB3,” Bichell said. “That may have some developmental effect people didn’t really anticipate before. It may have something to do with the eye and vision and how that whole connection in the brain works.”
Kang believes eye color may be an easily noticeable biomarker for GABRB3 mutations. The findings reported this week may encourage doctors to do more eye exams, called ERG tests, on children suspected of having Angelman syndrome. This could lead to earlier diagnosis, and possibly even treatment.
The discovery could also apply to epilepsy, as many patients with epilepsy experience eye problems, Kang added.
Bichell, who recently earned her Ph.D. in Neuroscience, soon will begin a new job as director of the Angelman Biomarkers/Outcome Measures Alliance. The alliance supports research aimed at identifying biomarkers and outcome measures that can help patients and families.
For now, she and Kang are still marveling in the serendipity of their group’s discovery.
“You go along doing science, and then every now and then you get a result that makes you go, ‘That’s funny.’ Those are the ones you have to pay attention to,” said Bichell.
“With help from the Vanderbilt community, we figured out what’s going on,” Kang added. “I think that’s the true spirit of being a scientist. We see many beautiful things from the community along the journey.”
This research was supported in part by National Institutes of Health NS082635 and ES007028.