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4.14.2015

Discovery of Critical Gene Mutation Linked to Hereditary Deafness

A gene mutation causing a form of hereditary deafness has been identified by an international team of researchers led by Xuezhong Liu, M.D., Ph.D., Leonard M. Miller Professor and Vice Chair for Research in Otolaryngology and Director of the Center for Hereditary Deafness at the University of Miami Miller School of Medicine. Investigators identified the mutation in gene DCDC2a by sequencing the genomic DNA of members of a multi-generational Tunisian family with a long history of profound deafness.

This discovery has wide implications for the future detection and treatment of congenital deafness, as DCDC2a appears to be crucial for the development and function of the sensory component of hair cells in the inner ear that are essential for human hearing. These findings were recently published online and on the current cover of the journal Human Molecular Genetics.

“This is another successful story on gene identification and ongoing characterization of their functions, which provides valuable insight into the molecular mechanisms of deafness,” said Liu, who co-authored the study with a host of researchers from the University of Miami Department of Otolaryngology and The Center of Biotechnology of Sfax in Tunisia led by Saber Masmoudi, Ph.D.

Among the study’s top findings, it revealed that the DCDC2a mutation alters the length of critical rod-shaped structures (kinocilium) that sit at the apex of hair cells and are essential to the stereocilia bundles’ organization and ability to process sound waves. The uncovered mutation is the first to be associated with the length regulation of the kinocilium.

“This finding provides additional basis for genetic diagnosis and the development of multiple gene screening panels for deaf patients, as well as the development of therapeutic interventions, such as gene and stem cell-based therapies,” said Liu, whose research center is among the top National Institutes of Health-funded centers for hereditary hearing loss in the U.S. and has discovered 15 percent of the new gene markers for hearing loss.

“Identifying the mechanisms of congenital deafness will help us determine the right time and tool for future therapies,” he added. “This most recent discovery will bring us a step closer to understanding the biological and cellular mechanism of how the human ear works and conveys sound to the brain.”

To characterize the effect of this deafness-causing mutation, researchers used a combination of molecular and cellular-based approaches applied to rat inner ear sensory tissue, as well as a zebrafish model.

“The increasing knowledge that we will gather on the cellular function of DCDC2a will be used to develop treatments to combat a wide range of congenital hearing defects,” said M’hamed Grati, Ph.D., assistant research professor, who co-led the study and began investigating the genetic causes of hearing loss among Tunisian families 22 years ago.

Hearing loss is the most common human sensory defect and affects one in nearly 500 newborns worldwide. The majority of cases are hereditary. However, Grati, who is Tunisian, said that the high rate of intermarrying among Tunisian families increases chances of disease, including deafness, among them.

Fred F. Telischi, M.D., professor and James R. Chandler Chair of Otolaryngology, said, “The discovery was remarkable and shows the level of dedication and expertise in the Miller School’s Department of Otolaryngology.

“The discovery is the first example of a human disease caused by a mutation in the DCDC2a gene,” he said. “This finding emphasizes the importance of genetic approaches for dissecting the root causes of hearing impairment.”

Furthermore, the compilation of data on DCDC2a is increasingly showing the gene’s importance, as recent studies have shown linkages to liver and kidney function.

“Our findings together with others clearly show the importance of DCDC2a’s regulatory role in many ciliated human organs,” said Liu.

Additional study collaborators at UM included Zhongmin Lu, Ph.D., associate professor in the Department of Biology (headed the zebrafish aspect of study); Qi Ma, Ph.D., senior research associate; Denise Yan, Ph.D., research assistant professor; Rahul Mittal, Ph.D., assistant scientist; biology student Alexandra DeSmidt; Amjad Farooq, Ph.D., associate professor of biochemistry; and Susan Blanton, Ph.D., associate professor of neurology and Associate Director of Communications and ompliance and Executive Director of the John P. Hussman Institute for Human Genomics.

Study researchers at the Center of Biotechnology of Sfax included Imen Chakchouk, Ph.D. student, Mariem Bensaid, Ph.D., Nouha Turki, M.D., Aissette Baanannou, Ph.D., and Nabil Driss, M.D. Masmoudi led the original gene mapping work of the family.

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