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NIJMEGEN, NETHERLANDS- A European research team has identified a genetic defect which appears to underlie the most common cause of deafness.

While as many as one in 1,000 births produce a baby with genetically determined deafness, little has been known of the causative genes. The most common form of inherited deafness, known as X-linked mixed deafness, or DFN3, involves defects in the stapes, a middle ear bone. The stapes, commonly called the stirrup, is an ossicle in the middle ear that articulates with the incus (another bone also called the anvil).

Linkage analysis and molecular biology studies narrowed the search for the responsible genes to x- chromosome 21. A team of Dutch and British researchers have now identified a genetic mutation potentially responsible for DFN3. The researchers report finding mutations in the gene Brn4, which encodes a transcription factor, expressed during development of the ear.

The researchers found the mutation in five unrelated patients with DFn3, but in one of 50 non-deaf controls. Using yeast chromosomal cloning techniques, the researchers were able to predict a location for the gene to a 500 kb region of chromosome 21. This coincided with the location of a gene called Brain4 (also called Pou3f4). Animal studies had shown this gene to be involved with development of the brain, neural tube and ear.

This chromosomal region has also been shown to be conserved between mice and humans. The researchers confirmed the human localization of the gene using a variety of techniques including polymerase chain reaction and Southern DNA blotting. This allowed further localization of the gene. . They were then able to amplify the human Pou3F4 sequence and create a probe.

The team then searched for mutations of the gene by examining DNA from people with and without X-linked deafness. Single strand conformation variants were found in patients with deafness but not in controls. IN some of the deaf patients mutations were found which did not involve the Pou3F4 gene. This could indicate that in some cases DFn3 is caused by non-coding or regulatory sequences elsewhere on the chromosome. It is also possible that such alterations may affect the overall chromosome structure, affecting expression of Pou4F4, the researchers notes.

"We have demonstrated that DFN3 is correlated with mutations that affect the POU3F4 protein. At least five POU domain genes are expressed in different parts of the developing inner ear. Defects of POU domain genes may play a major role in the etiology of nonsyndromic hearing impairment," notes Dr. Yvette J.M. de Kok, University Hospital in Nijmegen, Netherlands

Deafness can result from a variety of injuries or diseases before or after birth. Hearing loss involving the external auditory canal or middle ear is called conductive, while that involving the inner ear is called sensorineural. Conduction deafness involves conditions preventing the sound waves from being transmitted to the auditory receptors. Sensorineural deafness involves damage to the nerves and/or the inner ear. X-linked deafness involves elements of both conductive and sensorineural disease.

For a more detailed description of this research please refer to Science, v.267, 2/3/95, Kok et al.

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