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
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.”