Eric Turner, MD, PhD, of the Center for Integrative Brain Research at Seattle Children’s Research Institute has his sister and her pet rat to thank for his most recently-published study which identified a new kind of gene mutation which causes ear malformations in rats and mice. Findings from the study are expected to help researchers identify the gene mutations which cause these types of malformations in humans.

Dumbo rats from a lab at Kyoto University

Dumbo rats, courtesy of Takashi Kuramoto, Kyoto University

“Science sometimes proceeds by lucky guesses,” said Turner.  And in this case, science moved forward after a chat with his sister and subsequent collaborations with study co-author Tim Cox, PhD, one of many craniofacial experts at Seattle Children’s who specialize in the treatment of cleft lip and palate, craniosynostosis, craniofacial microsomia and other complex craniofacial conditions like ear malformations.

Turner was based at the University of California San Diego several years ago, conducting research on the sensory nervous system in dumbo mice.  The mice are named as such because they have prominent, low-set ears and are reminiscent of Dumbo, the baby elephant with enormous ears made famous in the 1941 animated Walt Disney film.

Lely Quina, who worked in Turner’s lab, found that dumbo mice have a developmental defect in the geniculate ganglion—an L-shaped collection of fibers and sensory neurons located in the facial canal of the head—and  its associated nerve, which provides sensation in the area around the ear.   These defects result from a mutation in a transcription factor called Hmx1. Although the discovery did not explain the reason for the ear malformation, it was a start to asking questions about the possible cause.

“Transcription factors attach to DNA and turn other genes off and on,” said Turner. “It’s like switching a light on or off. While a fetus is developing in the mother’s womb, transcription factors orchestrate developmental processes that determine if the fetus will have certain characteristics.”

Turner’s sister happened to mention to him that her family had a new dumbo rat.  He’d never heard of the dumbo rat, but after their discussion, he visited a rat breeder to get DNA samples from a few dumbo rats to see if they had a similar mutation to the dumbo mice.  A student in his lab sequenced the Hmx1 gene coding sequence from these dumbo rats, but didn’t find any mutations.  Turner decided to put his entire dumbo rat and mice ear malformation research project on the back burner since the research wasn’t netting the results they thought they might find.

End of story?  Not quite.  Two years ago, Turner read a study by a team led by Takashi Kuramoto, PhD, a geneticist from Kyoto University. The team found that there was indeed a mutation near the Hmx1 gene that caused the dumbo rat ears to have their distinctive shape.

“We realized that we had initially identified the gene causing the ear malformations, but we were thinking of the wrong kind of mutation. The Kyoto University team helped put us on the right track,” he said.

Around the same time, Turner and Quina landed at Seattle Children’s Research Institute and began collaborating with Cox and the craniofacial research team.  They studied dumbo rat embryos supplied by the Kyoto researchers and compared them to dumbo mice.

“What we found was quite remarkable,” Turner said.  “The Hmx1 protein is expressed normally in most places in the rat embryo, but it is specifically missing from the cells that contribute to the development of the ear.  This suggests a mutation in a regulatory region of the DNA rather than the protein-coding part of the gene.”

Turner said this project evolved at Seattle Children’s Research Institute in a way that it never would have at his previous institutions.  “That’s mainly because we have thrown together investigators interested in different kinds of problems—brain development and craniofacial birth defects—in close proximity, and stirred them around to see what kind of new ideas can be generated,” he said.

Cox and his team are gathering the resources to study the genetics of ear malformations in hundreds of children, and he said he hopes to connect insights from the dumbo rat research to human ear malformation defects in the future.

“Deletion of a conserved regulatory element required for Hmx1 expression in craniofacial mesenchyme in the dumbo rat: a newly identified cause of congenital ear malformation,” was published in the November/ December issue of Disease Models & Mechanisms.