Miller School Researchers Identify Gene Essential to Normal Inner Ear Development

A Miller School of Medicine research team led by Mustafa Tekin, M.D., a professor in the Dr. John T. MacDonald Foundation Department of Human Genetics who has been exploring the genetics of deafness for more than a decade, has identified a previously unrecognized gene, ROR1 (receptor tyrosine kinase-like orphan receptor 1), that is essential for the development of the inner ear and hearing in humans and mice. Their findings were recently published in PNAS (Proceedings of the National Academy of Sciences).

The inner ear is a vertebrate organ of delicate and complex architecture that translates sound into electrical signals deciphered by the brain. Despite recent progress in identifying genes that determine many forms of hearing loss — the most common sensory disorder — the genetic basis of inner ear anomalies has remained largely unknown. Tekin’s team’s expertise in identifying and characterizing deafness genes led to a $2 million NIH grant to identify the genetic causes of inner ear anomalies, which in turn led to the discovery of ROR1.

The researchers used a genetic approach to associate a mutation of ROR1 with inner ear anomalies and deafness in humans. Characterization of Ror1 mutant mice reveals fasciculation deficiencies of spiral ganglion axons and disruption of sensory hair cell synapses and peripheral innervations.

“While there are a number of successful animal studies to identify molecular components of inner ear development, mutations in only a few animal genes so far have been shown to cause inner ear anomalies in humans,” said Tekin. “We took a reverse approach starting from affected individuals to find genes relevant to human inner ear development.”

Oscar Diaz-Horta, Ph.D., a postdoctoral fellow at the John P. Hussman Institute for Human Genomics, was first author of the report.

“The ROR1 study was very exciting from the beginning,” he said. “The genetic data generated by whole exome sequencing pointed toward a mutation as the potential cause of deafness. To demonstrate causality, we needed to provide strong functional evidence, especially because the variation was detected in a small family with only two affected individuals.

“When we found out that the mutation was affecting the subcellular localization of ROR1, our expectations multiplied,” he added. “We became confident that ROR1 was a novel deafness gene following additional hearing tests performed on Ror1 mutant mice obtained from our collaborators at the University of Kobe in Japan.”

Diaz-Horta continued, “Another captivating part of the study began as we studied the underlying molecular function of ROR1 because its function in hearing was unknown entirely. Hearing tests performed on the affected individuals indicated auditory neuropathy, which led us into our initial investigation. Further characterization of the mutant mice definitely implicated Ror1 in the proper auditory hair cell innervation and normal hearing.”

Tekin said, “We are characterizing genes and proteins for the normal function of the inner ear. We need to understand the players in normal hearing, and then how we can prevent and even treat genetic hearing loss beyond what is currently available.”

Hearing loss affects approximately one in 500 newborns. Genetic etiology is present in more than half of the cases with congenital hearing loss. Most known gene mutations affect genes that perform specific functions in the inner ear, where sound waves are converted to electrical signals. Inner ear anomalies resulting from disrupted embryonic development of the inner ear are associated with hearing loss in up to one-fourth of affected children.

“This has implications for clinical diagnostics and genetic counseling,” said Tekin. “The knowledge we gain from this study will help us empower affected individuals and families to make informed reproductive decisions.”

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