Scientists have identified a genetic mutation in humans that affects the severity of hearing loss caused by a mutation of another gene. National Institute on Deafness and Other Communication Disorders (NIDCD) scientists Drs. Julie Schultz and Andrew Griffith and co-authors at NIH* and the Mayo Clinic Foundation reported their findings in the April 14 issue of The New England Journal of Medicine.

Genetic mutations are estimated to cause at least one half of all cases of congenital or childhood-onset hearing loss. Individual variations in the severity of hearing loss are common and typically attributed to environmental factors and modifier genes ¡ª genes that alter the clinical expression of a mutation in another gene.

In the current study, five adult siblings from the same family were found to possess a mutant form of the gene that encodes for the protein cadherin 23, which is required for the development of hair cells in the inner ear. However, the degree of hearing loss among the siblings varied. While three of the five individuals had severe to profound deafness, the other two had hearing loss only in the higher frequencies. This variability suggested the action of a modifier gene.

NIDCD scientists, led by Drs. Thomas Friedman and Konrad Noben-Trauth, had previously discovered that mutations of the cadherin 23 gene cause hearing loss in humans and mice. Dr. Noben-Trauth and his co-workers had also shown that alterations of another gene, ATP2B2, can affect the severity of hearing loss caused by a cadherin 23 mutant gene in mice. ATP2B2 encodes for a key cellular protein, known as a plasma-membrane calcium pump, that is thought to be important for regulating calcium concentrations both around and within hair bundles of hair cells. On the outside of the hair bundle, calcium is required to maintain the correct structure of the hair bundles and on the inside it may act as an important signaling or regulatory molecule.

In this study, Dr. Schultz and her co-workers found that a mutant form of the human ATP2B2 gene, called V586M, accounted for the more severe hearing loss in the siblings who were profoundly deaf. The two siblings with better hearing were found to have normal copies of the gene. About 1 in 20 Caucasians are carriers of V568M.

Although V568M does not cause hearing loss, the current findings suggest that V568M may exacerbate hearing loss caused by environmental factors or other genetic influences. Further research is needed to determine the role of V568M and other mutations of the calcium pump in hearing loss associated with advanced age, exposure to loud noise, and mutations in other deafness genes.

*This research was also supported by the National Heart, Lung, and Blood Institute, another component of the National Institutes of Health.