TAU Trends in Research

June 1999

A Defective Gene that Causes Progressive Hearing Loss

The chirping of a bird outside your window in the morning is so loud that it wakes you up but gradually, by your late teens, birds don't seem quite as loud as they used to be. By age 40, you can hardly hear them without a hearing aid. Although age-related hearing loss is a widespread problem, affecting 50% of the elderly population, in some cases genetic mutations lead to far earlier inherited hearing losses, such as the early-onset case described above. The many social implications of hearing losses include isolation, loneliness and occupational and educational underachievement in societies largely designed for only normal hearing.

Despite its high prevalence and importance, little is known about the molecular events leading to deafness. To help understand the biological basis of hearing loss, TAU researcher Dr. Karen Avraham has been searching for the genes involved in normal hearing and in hereditary hearing impairment. A large Israeli family with over 100 members (Family H) exhibiting progressive hearing loss was included in this study. Six months after collecting blood from twenty-three family members, in collaboration with US colleagues. Dr. Avraham identified the approximate location of the Family H deafness gene on chromosome 5.

Although no human genes which might lead to deafness in this family had been previously found in this chromosomal region, a close inspection of the homologous region on mouse chromosome 18 revealed the presence of the Pou4f3 gene. This gene is specifically and uniquely expressed only in the hair cells (sensory cells) of the inner ear. When Pou4f3 is removed from the mouse genome by gene-targeted mutagenesis, profound deafness results.

All three collaborating laboratories coordinated their efforts and worked literally around the clock to find, isolate and characterize the human homologue of the Pou4f3 gene in record time. This led to the identification of the mutation in the human Pou4f3 genes which causes hearing impairment in Family H. Within weeks, their continuing studies were published in Science (March 1998), and disseminated throughout the international scientific community.

A portion of the Family H pedigree. The dominantly inherited hearing-loss genetic mutation was traced back five generations to an ancestor born in 1843. Each child has a 50% chance of inheriting the mutant gene, shown in red on the chromosome and by colored circles (females) or squares (males) on the family tree.
Family H pedigree
Actually, each of the hearing-impaired members of Family H carry two forms of the defective gene: one normal and one mutant. The single normal gene appears to be adequate for awhile, since hearing is normal until around age 18. The mutant form of the gene then seems to take over, preventing the protein encoded by the normal gene from functioning properly.

The crucial protein coded in the Pou4f3 gene is a transcription factor, which controls the expression of other genes by binding to them and turning them on or off. In the inner ear, the mutant proteins do not properly regulate their target genes; but understanding the activity of this new gene should help scientists better understand the intricate function of the inner ear.

The next step is to determine whether the Pou4f3 gene is also involved in congenital or age-related hearing loss in other deaf individuals and, whether knowledge of the Pou4f3 gene's normal function can suggest ways to alleviate more common forms of deafness.

For further information please contact:

Karen B. Avraham, Ph.D.
Department of Human Genetics & Molecular Medicine
Sackler School of Medicine
Tel Aviv University
Ramat Aviv, Tel Aviv 69978
Tel: 972-3-640-7030
Fax: 972-3-640-9900
E-Mail: karena@post.tau.ac.il

TAU Trends in Research Last modified: June 27, 1999