Laboratory of Molecular Genetics, National Institute
on Deafness and Other Communication Disorders, National Institutes of Health,
5 Research Court, Rockville, Maryland
20850, USA. friedman@nidcd.nih.gov
Sound is a well-understood, physical phenomenon. How we perceive sound
and make sense of complex auditory stimuli is a different matter altogether.
Genetic approaches, however, have provided a powerful strategy to dissect
auditory function and to some extent, overcome the challenge posed by the
inaccessibility and scant quantities of cochlear neurosensory tissue lying
deep within the temporal bone. Although remarkable progress has been made
in identifying genes causing hearing loss, correlating the functions of those
genes with specific auditory processes or pathways is not always straightforward.
On page 363 of this issue, Shin'ichiro Yasunaga and colleagues report the
latest 'deafness' gene1. While its function has yet to be determined,
its sequence and expression in the inner hair cells of the cochlea provide
some intriguing clues.
The cochlear neuroepithelium includes inner hair cells (
Fig. 1). These transduce sound into electrical impulses that are transmitted
to the central nervous system. While transducing sound, the cochlea faithfully
preserves the frequency information of the stimulus. It accomplishes this,
in part, by a tonotopic organization of the neurosensory tissue that lies
along its length: one end of the cochlea is stimulated by high-frequency sounds
and the other is stimulated by low frequencies. This physical distribution
of 'sensitivity' to frequencies is similar to that of a piano except that,
instead of less than 100 keys, there are more than 3,000 notes that the cochlea
can perceive. This organization does not fully account, however, for the high
degree of resolution of frequency information that the human perceives.
Figure 1. Diagram of the human ear, including cross sections of the cochlea showing
three outer hair cells and one inner hair cell in the organ of Corti.
The basilar membrane vibrates in response to sound waves, which results
in deflection of the hair cell stereocilia bundle by the tectorial membrane.
Sound transduction occurs via the inner hair cells, which form synaptic connections
with afferent nerve fibres of the cochlear ganglion. Displacement of outer
hair cell stereocilia results in rapid, reversible shortening of the cell
that amplifies the motion of the basilar membrane2,
3. Figure
adapted from those appearing in refs 4 and 5.
There are success stories in which deafness genes have been linked to cochlear
function, physiology and development. Recently, a 'deafness' gene that resides
at the nonsyndromic dominant deafness locus DFNA2 was identified as
one that encodes a novel potassium channel (KCNQ4; 6) and is expressed in the outer hair cells of the cochlea. The
connexin genes GJB2 and GJB3 and the potassium channel subunit
genes KCNQ1 and KCNE1 probably have important roles in potassium
homeostasis in the auditory system; mutations in these genes can cause sensorineural
hearing loss. Furthermore, mutations of KCNE1 (JLNS2) and
KCNQ1 (JLNS1) can cause cardiac conduction abnormalities in addition
to hearing loss7.
Striking a nerve The gene discovered by Yasunaga et al., OTOF, encodes a protein
termed otoferlin; its mutation causes recessive deafness phenotype DFNB9
in four Lebanese families. Otoferlin contains three C2-like domains;
in other systems, C2 domains interact with phospholipids and proteins. In
the postnatal cochlea, otoferlin is predominantly located in sensory inner
hair cells, which contain special synapses called ribbon synapses. Otoferlin
is similar to other C2 domain-containing proteins, including the fer-1 protein
of Caenorhabditis elegans; the spermatids of C. elegans fer-1
mutants show impaired fusion of large vesicles within their plasma membranes.
Yasunaga et al. therefore propose that otoferlin is involved in synaptic vesicle
trafficking.
The relatively specific expression of mouse Otof in the inner hair
cells begs the question of how it is involved in functions specific to the
auditory sensory system. It is possible that otoferlin mediates synaptic transmission
within the cochlea, and hence, the auditory system's ability to tune itself.
If this hypothesis is correct, otoferlin should indeed be located in the synaptic
regions of hair cells.
The central nervous system performs the unique tasks of recognizing and
processing complex auditory stimuli such as speech, and localizing sounds
in the environment8. It should not be ignored in the genetic
dissection of deafness, nor when speculating on otoferlin function; neither
OTOF expression nor frequency tuning are limited to the cochlea. Otof
expression in mouse brain was detected by RT-PCR analysis, although it
is impossible to infer the specificity and levels of expression from such
an analysis. Elucidating the location of Otof within the central nervous system
is clearly in order, with a specific view to determining its expression in
the the anatomic pathways of the central auditory system. Hopefully additional
mutations in OTOF will be identified—if so, careful analyses
of the phenotypes may shed light on its role in the central nervous system.
Clues from the clinic There have been few thorough auditory phenotypic characterizations of families
segregating identified deafness mutations. Many of these families are from
geographically isolated areas and are not amenable to thorough clinical evaluations.
Accordingly, there is little by way of specific data on the neurologic or
audiologic phenotypes of the individuals described by Yasunaga and colleagues.
Thorough clinical and electrophysiologic examinations may reveal neurologic
abnormalities that were initially undetected, and help to elucidate the function
of otoferlin. Peripheral auditory defects may be differentiated from central
defects by audiologic methods including routine speech audiometry or auditory
brainstem response testing. Although these methods are not useful in cases
of total deafness, they might delineate the affected region(s) of the auditory
system in cases of less severe hearing loss.
It may well be that many forms of 'nonsyndromic' genetic deafness have
associated non-auditory features. Initially one may not know exactly where
or how to look for these, but once the expression profile of a given deafness
gene is determined, the opportunity to refine phenotypes should be explored.
There is already an example that vindicates this strategy. The original
DFNB4 family was subsequently shown to have Pendred syndrome9.
As the era of gene mapping and cloning proceeds, functional clues from
many of the newly identified 'deafness' genes are being pieced together. There
remains a list of unexplained auditory system phenomena such as outer hair
cell motility, and a growing catalogue of gene products necessary for hearing.
Only a few DFNA and DFNB genes have been linked to specific roles in auditory
function, and many deafness genes are currently unknown (see
Fig. 2 for the latest locus map). Nevertheless, each new 'deafness'
gene is received with fanfare in anticipation that a novel molecular correlate
of auditory function may eventually be discovered, and DFNB9 is no
exception. With the identification of every hereditary hearing loss gene,
we come closer to making sense out of sound.
Figure 2. Cytogenetic locations of genes for syndromic and nonsyndromic hearing
loss illustrated on a human male karyotype.
Hearing loss occurring as an isolated disorder is referred to as nonsyndromic
whereas it is referred to as syndromic when co-segregating with any non-auditory
abnormalities. Gene symbols for independently mapped hearing loss loci that
are discovered to be due to allelic mutations are separated by a slash (/).
For example, the families used to map DFNB21, DFNA8 and
DFNA12 on chromosome 11q are all segregating alleles of TECTA,
which encodess-tectorin10,
11. An online compendium of
mutations of many of these genes can be found at the Human Genetics Mutations
Database (http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html). Additional
unpublished information about DFNA and DFNB loci can be found on the Hereditary
Hearing Loss web site (http://dnalab-www.uia.ac.be/dnalab/hhh).
-tectorin
