While "mapping genes that put the brain together," a Ph.D.candidate named David Bradley serendipitously identified amutated gene linked to a rare form of inherited deafness.
His unexpected finding is reported in the current issue of theProceedings of the National Academy of Science (PNAS) as "aand b thyroid hormone receptor (TR) gene expression duringauditory neurogenesis: Evidence for TR isoform-specifictranscriptional regulation in vivo."
Congenital deficiency of iodine, the thyroid hormone's primeelemental ingredient, is known to cause deafness in children.Recent research by Samuel Refetoff at the University of Chicagohas traced this hearing loss to a deletion on chromosome 3 ofthe thyroid hormone receptor's beta gene (TR-b).
Bradley's paper reports tracking this mutant gene to the innerear of rat embryos, precisely the site where the key organ ofhearing, the cochlea, begins to develop. The snail-shapedcochlea, the brain's hearing apparatus, is like a junction box inwhich acoustic signals go round and round the structure's two-and-a-half-turn spiral, and are then transduced into auditorynerve impulses for decoding in the brain.
TR beta enters the cochlea on day 12 of rat gestation, earlierthan expected, the PNAS paper reported. This stage is roughlyequivalent to that of 4-week-old human fetuses. In rats,cochlear embryonic development continues for several daysafter they are born. Human neonates come into the world withfully formed hearing. Their mature cochlea are equipped withsome 30,000 ultrafine hair cells. It is the acoustic vibration ofthese cilia that actually translates sound into hearing.
Like other neurons in the brain, the sensory hair cells don'tregenerate, but die off with time, which explains much of thecreeping deafness in a third of the aging population. The TR-bgene isoform encodes one of the proteins that seem to start theRNA transcription cascade, which populates the cochlea withhair cells. The gene's partial or total deletion, Bradleysuggested, causes the congenital sensori-neural deafness ofchildren who inherit the mutation from both parents.
"We saw more of that thyroid hormone receptor geneexpression in the developing inner ear than anywhere else inbrain development," Bradley told BioWorld. "And we were ableto correlate a mutation in one of those THR genes with a humansensory deficit, deafness, and that's quite unusual."
According to an editorial in PNAS, some researchers are tryingto understand the factors involved in hair-cell development inorder to stimulate regeneration from stem cells and reversethis type of hearing loss.
The embryonic cochlea is about a millimeter long, Bradley said.Working on his doctorate in the National Institute of MentalHealth's cell biology lab, he synthesized radiolabeled antisensenucleic acid probes to detect the transcribed RNA that encodesthe thyroid receptors on cells of interest. His substrateconsisted of frozen cochlear tissue sections 12 microns thick,probed by in situ hybridization to localize RNA's presence intypes of brain cells.
"There's still a long way to go," Bradley said. "Down the road,the identification of the specific transcription factors that turnthe genes on and off will help people understand how acomplicated organ like the inner ear is put together."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.