• Molecular process behind a form of deafness also may damage other organs

    An underlying molecular process that causes a genetic form of non-syndromic deafness also may put affected families at higher risk of damage to the heart, thyroid and salivary glands, according to a multi-national research team led by scientists at Cincinnati Children’s.

    The study, posted online Aug. 27, 2013, in the Journal of Clinical Investigation, was focused on finding possible treatments for DFNB49 non-syndromic hearing loss, an inherited condition caused by mutations in the gene TRIC. But the mouse model developed for the research demonstrated unexpected characteristics that suggest TRIC mutations also can damage cell structures in other organs.

    “Understanding the function of a deafness-causing mutation and the mechanism of disease progression is an important first step towards finding a therapeutic solution,” said Saima Riazuddin, PhD, senior investigator and a scientist in the Division of Otolaryngology / Head and Neck Surgery at Cincinnati Children's. “But our study on mice also suggests we should clinically evaluate affected individuals more thoroughly, as they may have some other and not very obvious clinical problems involving multiple organs.”

    To conduct their study, the researchers developed a first-ever “knock-in” mouse model of DFNB49 deafness by inserting mutations in the corresponding mouse version of the TRIC gene, known as Tric. This led to the loss of a critical protein called tricellulin in the mice.

    The loss of tricellulin disrupted the structure of  tight junctions in the epithelial cells of the cochlea in the inner ear. This affected the permeability of inner ear epithelia tissue, creating a possible channel that caused an imbalance in the quantity of ions and macromolecules. Researchers theorize this resulted in a loss of cochlear hair cells, leading to hearing loss in the mice.

    But the researchers also observed that their newly generated Tric-mutated mice had enlarged hearts, livers, spleens and kidneys. Finding enlarged nuclei in the cardiomyocyte cells of the mice suggests that the gene mutation in mice may be linked to myocardial hypertrophy – a dangerous thickening of the heart muscle.  

    “In previous studies, affected members of DFNB49 families did not reveal any other obvious conditions besides hearing loss, but the human families were not assessed to the same extent as the evaluation we conducted on the tricellulin mutant mice,” said Riazuddin. “In light of our current findings, we are beginning to understand the broader function of tricellulin, and this study will guide us for further follow-up clinical evaluations of affected families to help us understand their complete medical spectrum.”

  • Saima Riazuddin, PhD.
    Saima Riazuddin, PhD.