Wellcome Trust Sanger Institute study: Mutant mouse gene offers clues to progressive hearing loss in humans

LONDON—Researchers at the Wellcome Trust Sanger Institute have defined a mutation in the mouse genome that closely mimics progressive hearing loss in humans. The finding, detailed in a recent study published in the Public Library of Science's Genetics journal, could be used to give researchers gene candidates to study in human deafness, according to the researchers.

Using a mouse model to study deafness because of its similarity to the human auditory system, the researchers mapped the mutation to the mouse genome and quickly found a probable cause for hearing loss. The mutant mice carried a change in one letter of their genetic code in a gene called Atp2b2. Changing a specific C to a T in this gene stops it from producing a normal molecular pump that is needed to keep hair cells in the ear working efficiently by pumping excess calcium out of the cell, the researchers found.

They further observed that when one copy of the gene is affected, the pump works, but not well enough and hearing gradually fails. If both copies are affected, the pump hardly works at all and hearing is lost before birth, the researchers found.

Although little is known about the genes involved in common forms of progressive hearing loss, previous research has identified many genes involved in childhood deafness. Because these genes rarely contribute to hearing loss in humans, their role in progressive hearing loss is poorly understood. The new research is part of a systematic approach to identifying genes that play a role in hearing and deafness, says Wellcome Trust Sanger Institute Professor Karen Steel, a senior author on the study.

"We know of only a handful of gene variants involved in progressive hearing loss, identified over the past 15 years," Steel says. "We need a better approach to understanding hearing loss. This is one of the first fruits of that program."

Improving understanding of the molecular and cellular action of genetic variants will help researchers to develop improved diagnostics and treatments for humans, Steel says. But she cautions the work is still at a basic level, as researchers do not yet know how often this gene will be involved in human deafness. While improvement in diagnosis for individual families with hearing loss caused by mutations in this gene could be implemented very soon—depending only upon resources for clinical genetics services—the possibility of treatments will be on a longer timescale, Steel says.

"We plan to look for other genes involved in progressive hearing loss in the mouse and screen DNA samples from human populations to ask how frequently mutations in these genes are found associated with deafness," she says. "We also plan to ask if the mechanism by which hair cells degenerate in this mutant is common to other forms of progressive hearing loss, and if we can prevent hair cell degeneration, can we retain any auditory function despite the abnormal calcium pumping activity?"

The study, The Novel Mouse Mutation Oblivion Inactivates the PMCA2 Pump and Causes Progressive Hearing Loss, was published in PLoS Genetics on Oct. 31. In addition to the Wellcome Trust Sanger Institute, the study was conducted by researchers at the MRC Institute of Hearing Research; the Venetian Institute of Molecular Medicine; the Institute of Experimental Genetics in Neuherberg, Germany; and the University of Padua in Italy. DDN