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