Researchers Close in on Genetic Cure for Congenital Deafness
Researchers are a step closer in the quest to use gene therapy to enable people born deaf to hear, having uncovered a new role for a key protein.
The study, published in Molecular Biology of the Cell, focused on a large gene responsible for an inner-ear protein called otoferlin. Otoferlin mutations are linked to severe congenital hearing loss, a common type of deafness in which patients can hear almost nothing.
“For a long time otoferlin seemed to be a one-trick pony of a protein,” explained Colin Johnson, associate professor of biochemistry and biophysics in the Oregon State UniversityCollege of Science. “A lot of genes will find various things to do, but the otoferlin gene had appeared only to have one purpose and that was to encode sound in the sensory hair cells in the inner ear. Small mutations in otoferlin render people profoundly deaf.”
Because the otoferlin gene is too big as it normally is to package into a delivery vehicle for molecular therapy, Prof Johnson’s team explored the use of a shortened version.
Research led by graduate student Aayushi Manchanda showed the shortened version needed to have part of the gene known as the transmembrane domain, for a surprising reason: without it, the sensory cells matured slowly.
“That was surprising since otoferlin was known to help encode hearing information but had not been thought to be involved in sensory cell development,” Johnson said.
For years, scientists in Prof Johnson’s lab have been working with the otoferlin molecule and in 2017 they identified a shortened form of the gene that can function in the encoding of sound.
To find out if the transmembrane domain of otoferlin needed to be part of the shortened version of the gene, Manchanda shortened the transmembrane domain in zebrafish.
Zebrafish are a small freshwater species that is very popular as a research organism. They grow rapidly, from a cell to a swimming fish in about five days, and share a remarkable similarity to humans at the molecular, genetic and cellular levels due to the conservation of mammalian genes early in their evolution. Embryonic zebrafish are transparent and easily maintained, and are amenable to genetic manipulation.
“The transmembrane domain tethers otoferlin to the cell membrane and intracellular vesicles but it was not clear if this was essential and had to be included in a shortened form of otoferlin,” Manchanda said. “We found that the loss of the transmembrane domain results in the sensory hair cells producing less otoferlin as well as deficits in hair cell activity. The mutation also caused a delay in the maturation of the sensory cells, which was a surprise. Overall the results argue that the transmembrane domain must be included in any gene therapy construct.”
At the molecular level, Manchanda found that a lack of transmembrane domain led to otoferlin not properly linking the neurotransmitter-filled synaptic vesicles to the cell membrane, resulting in less neurotransmitter being released.
“Our study suggests otoferlin’s ability to tether the vesicles to the cell membrane is a key mechanistic step for neurotransmitter release during the encoding of sound,” Manchanda said.
Source: EurekaAlert!
