Hearing loss is the most common sensory deficit, affecting almost half of all people at some time in their lives. Clinically significant hearing loss is present in approximately 1 in 500 newborns, and inner ear malformations are diagnosed in up to 25 percent of those children.
A recent study led by genetic researchers at the University of Miami Miller School of Medicine has discovered the role of the gene GDF6 in early cochlear development. The article, titled “Long-range cis-regulatory elements controlling GDF6 expression are essential for cochlear development,” was published in May in the Journal of Clinical Investigation (JCI), one of the world's most cited and comprehensive multidisciplinary scientific journals.
“In over half of infants affected by sensorineural hearing loss, genetic factors are involved,” said study author Mustafa Tekin, M.D., a professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and a member of the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine. “To date, we know of over 100 genes that are linked to deafness. But they can explain only about half of cases with hearing loss.”
Contemporary research using animal models has focused on understanding the pathways and genes involved in the embryonic development of the hearing organ, the cochlea; the molecular mechanisms that govern early cochlear development in humans are poorly understood. Researchers concluded from their findings that the GDF6 gene plays a necessary role in early cochlear development and its disruption leads to deafness due to cochlear aplasia.
In their investigation, University of Miami researchers and their scientific counterparts in Turkey, led by Dr. Tekin, set out to understand the molecular components of early cochlear development and conducted a genetic study on congenital deafness associated with cochlear aplasia. Cochlear aplasia is the complete absence of the cochlea in the inner ear. It is a rare anomaly which accounts for about 3 percent of cochlear malformations.
The study included three affected and eight unaffected individuals from two Turkish families. Researchers first conducted analysis of the sequenced DNA of the participants and their family members and did not detect a DNA variant involving a gene. They eventually discovered two deletions in a genomic region—the intergenic—that was away from the genes. These deletions were in the same topologically associating domain (TAD) or “chromosome neighborhood” as the GDF6 gene.
To demonstrate that GDF6 is involved in cochlear development, the team performed experiments to modify otic lineage cells from human induced pluripotent stem cells (iPSC). To determine if there were expression differences between affected and unaffected individuals, researchers derived iPSC lines from fibroblasts, cells that give rise to connective tissue, from the affected and unaffected individuals and modified into early otic lineage cells to determine the expression of specific markers in different stages of cochlear development. The results suggested that GDF6 expression begins during the early stages of inner ear development and that the detected intergenic deletion reduces its expression.
Finally, to show that disruption of GDF6 affects cochlear development, the team evaluated a GDF6 knock-out mouse model. This particular mouse model does not survive postnatally and shows fusion of the carpal and tarsal joints, coronal craniosynostosis, and middle ear defects. A cochlear defect had not been shown.
The researchers demonstrated that GDF6 is highly expressed in the cochlea during development and in adult mice. The subsequent dissection of the GDF6 mutant mouse and wild type mouse inner ears to assess anomalies indicative of the human characteristics showed defects in the mutant mice with cochlear aplasia.
While gene therapy efforts are underway, currently there are no cures for hearing loss and affected individuals are often treated with hearing aids or cochlear implants. Researchers believe that understanding the mechanisms governing early cochlear development may lead to therapeutic interventions.
Guney Bademci, M.D., assistant professor in the Dr. John T. Macdonald Foundation Department of Human Genetics, is the first author. Other collaborators from the University of Miami include Derek M. Dykxhoorn, Ph.D., associate professor, and Katherina Walz, Ph.D., associate professor, both in the Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics.