Mouse study reveals potential new treatment for inherited deafness

Illustration of three DNA helices
The researchers used small molecules to block histone deacetylation, the process by which the DNA-binding protein REST inactivates gene expression. (Darwin Laganzon)

A decade ago, NIH researchers studying an inherited type of deafness in a single extended family managed to identify the mutation responsible. They named the family's condition DFNA27 deafness, after the region on chromosome 4 where the mutation resides. But while they were able to narrow the location of the abnormality down to a dozen or so genes, its exact location stayed a mystery—until now.

In a mouse study, the NIH scientists pinpointed that location, shedding light on the mechanism that causes the condition, as well as a potential treatment for humans. The NIH researchers teamed up with Botond Banfi, M.D., Ph.D., and Yoko Nakano, Ph.D., of the University of Iowa, after the latter pair discovered a link between deafness, the REST gene in mice and its human equivalent, located in the DFNA27 region.

The missing piece was exon 4, a previously overlooked exon in the REST gene, which codes for a protein of the same name. The REST protein's normal job is to switch off neuronal genes in non-neuronal cells. Prior work has overlooked exon 4 because it is not edited into REST mRNA, the instructions for generating the REST protein, according to a statement.

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The researchers deleted exon 4 from the REST gene in mice, which killed their inner ear hair cells, making the mice deaf. Together, the NIH and University of Iowa teams found that the DFNA27 mutation lies near exon 4, which prevents the inactivation of REST in hair cells, resulting in many cells that should be activated being switched off instead. 

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"We found that incorporating exon 4 into the REST mRNA acts like a switch in sensory hair cells. It turns off REST and allows many genes to be turned on," Banfi said in the statement. "Some of these turned-on genes are important for hair cell survival and hearing." 

REST is a DNA-binding protein that blocks gene expression through a process called histone deacetylation. The researchers used small molecules to hinder this process, thereby negating the effects of REST and restoring some hearing to the mice. The study appears in the journal Cell.

As many as half of all cases of deafness are caused by genetic defects, sparking a range of ideas for correcting hearing loss by targeting wayward genes. Another potential treatment for inherited deafness is CRISPR-Cas9 gene editing, for example. Scientists at the Howard Hughes Medical Institute have used a "genome editing cocktail" to prevent hearing loss in mice with a mutation called Tmc1. If successful in humans, it could be used to treat people with the same mutation, who progressively lose hair cells in their inner ears.

The small molecules developed for the NIH-led mouse study improved their hearing of low-frequency sounds and saved some of the hair cells in their ears, said Thomas Friedman, Ph.D., chief of the Laboratory of Human Molecular Genetics at the NIH's National Institute on Deafness and Other Communication Disorders, in the release. "If additional studies show that small-molecule-based drugs are effective in treating DFNA27 deafness in people, it's possible that using similar approaches might work for other inherited forms of progressive hearing loss," he said.