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Human Molecular Genetics Pages 1589-1597  

The fundamental and medical impacts of recent progress in research on hereditary hearing loss
Introduction
   Hereditary hearing loss
   Structure and function of the ear
Syndromic Hearing Loss
Non-Syndromic Hearing Loss
Insights Into The Development And Physiology Of The Ear
Medical Impact Of Deafness Research
References

The fundamental and medical impacts of recent progress in research on hereditary hearing loss

The fundamental and medical impacts of recent progress in research on hereditary hearing loss

Vasiliki Kalatzis and Christine Petit*

Unité de Génétique des Déficits Sensoriels, CNRS URA 1968, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France

Received June 9, 1998

What would define real progress in the field of deafness research in fundamental and medical terms? In fundamental terms, progress would be measured by an improvement in our knowledge of the development and physiology of the ear. In medical terms, progress would lead to the division of the broad category of hearing defects into distinct clinical entities or subclasses, the collection of epidemiological data, the creation of molecular diagnostic tests, the improvement of genetic counselling services and the development of new therapeutics. In this review, we will introduce some general considerations on hereditary hearing loss and on the structure and function of the ear, present the rapidly emerging data on the molecular basis of syndromic and non-syndromic forms of hearing loss and comment on relevant recent progress in this field of research. Generally speaking, the isolation of genes underlying hereditary hearing loss has, as yet, had little impact on our understanding of the biology of the ear, whereas it has made major contributions to the medical field, in particular due to the recognition of two genes, Cx26 and mitochondrial 12S rRNA, as frequently underlying cases of non-syndromic hearing impairment.

INTRODUCTION

Hereditary hearing loss

The overall impact of hearing impairment is greatly influenced by the severity of the hearing defect and by the age of onset. If the defect is severe and presents in early childhood, it has dramatic effects on speech acquisition and thereby cognitive and psychosocial development. A hearing defect appearing at a later age can also severely compromise the quality of life as it results in the isolation of an affected individual.

Deafness can be due to genetic or environmental causes or a combination of both. The main contributing environmental factors are meningitis, mumps, perinatal complications, materno-fetal infections (toxoplasma, rubella and cytomegalovirus infections), acoustic trauma and ototoxic drugs. Approximately 1/1000 infants are affected by severe or profound deafness at birth or during early childhood, i.e. the prelingual period. In developed countries, it has been estimated that ~60% of the cases without an obvious environmental origin have a genetic basis (1). Although these figures need to be considered with caution, the proportion of cases with a genetic origin is expected to continuously increase as public health improves. A further 1/1000 children become deaf before adulthood and these forms are usually less severe and progressive. The proportion of such cases with a genetic basis is not well documented. Finally, for the late onset forms, 0.3 and 2.3% of the population manifest a hearing loss >65 decibels hearing level (dB HL) between the ages of 30 and 50 years and between 60 and 70 years, respectively. These forms are generally considered to result from a combination of genetic and environmental causes, thus explaining the lack of epidemiological data available concerning the genetic origin. One particular, and frequent, form of late onset deafness, otosclerosis (see below), deserves to be highlighted, as there is evidence supporting a significant genetic basis.

Structure and function of the ear

The adult mammalian ear is a highly intricate organ. It is made up of three distinct parts, the external, middle and inner ear, which function as one unit (Fig. 1). The external ear is the sound collecting funnel and the middle ear transmits the sound to the inner ear, where it is processed. In addition to sound processing, the inner ear has another function, which is the control of equilibrium. The external ear comprises the auricle and the external auditory canal, which transfers the sound to the tympanic membrane. The middle ear consists of a chain of three ossicles, the malleus, incus and stapes, which collect the vibrations received by the tympanic membrane and transmit them to the oval window of the inner ear. The inner ear is composed of two fluid-filled labyrinths. The membranous labyrinth is an elaborate system of endolymph-filled, epithelium-lined chambers and canals. The membranous labyrinth lies within the temporal bone in a series of similar shaped cavities constituting the bony labyrinth. The narrow space between the bony and membranous labyrinths is filled with perilymph. The sound processing portion of the membranous labyrinth is the snail-shaped cochlea duct, which comprises 2.5 turns and can process 20 Hz-20 kHz sound in humans and 1.75 turns with a capacity of 1-100 kHz in mice. The remaining portion is collectively referred to as the vestibular apparatus. It is composed of the saccule and utricle, which respond to linear acceleration, and the three semicircular ducts, which respond to angular acceleration. In this way, the vestibular complex detects head position and movement and thus controls equilibrium.


Figure 1. Schematic representation of the mammalian inner ear. The mammalian ear is composed of three compartments: the outer ear made up of the auricle and external auditory canal, the middle ear made up of the ossicles within the tympanic cavity and the inner ear made up of the vestibular apparatus and the cochlea. Modified and reprinted with permission from Petit (17).

The sensory epithelia of the inner ear are the auditory transduction sensory apparatus of the cochlear duct, the organ of Corti (Fig. 2), the maculae of the utricle and saccule and the cristae ampullae of the semicircular canals. These structures consist of a highly organized array of supporting and sensory hair cells, the latter carrying a distinct bundle of actin-filled stiff microvilli, called stereocilia, on their apical surface. The three types of inner ear neuroepithelia are covered by an acellular gelatinous membrane: the tectorial membrane over the organ of Corti, the otoconial membranes over the maculae and the thick, dome-shaped cupula over the cristae. Sound transfer or head movements cause a displacement of these acellular membranes relative to the neuroepithelia in the cochlear duct and vestibular complex, respectively. This displacement provokes a deflection of the sensory hair cell stereociliary bundles, which, in turn, opens up the mechanotransduction channels located at the tip of the stereocilia. It has been proposed that the tip link, a filamentous connection attaching the tip of a stereocilium to the nearest taller stereocilium, is the gating spring for opening of these transduction channels (2). The resultant influx of potassium, from the potassium-rich endolymph through the mechanotransduction channels, alters the membrane potential which results in the release of a synaptic transmitter from the hair cell. On neurotransmitter release, an afferent nerve fibre at the base of the hair cell transmits to the brain a pattern of action potentials encoding certain characteristics of the stimulus, such as intensity, frequency and time course (3).


Figure 2. The organ of Corti of the cochlear duct (scala media). The organ of Corti is situated on the floor of the endolymph-filled cochlear duct and is made up of an array of sensory (ihc, ohc) and supporting (p, d, h) cells and the overlying tectorial membrane (tm). Each sensory cell is capped by a stereociliary bundle which is deflected by shearing of the tm. The organ of Corti is flanked by the inner sulcus cells on the medial side and the Claudius' cells (c) on the lateral side. The stria vascularis (sv) on the lateral wall of the cochlear duct is responsible for the unique ionic composition of the endolymph. The cochlear duct is surrounded above and below by perilymph-filled spaces (scala vestibuli, scala tympani). sg, spiral ganglion; cn, cochlear nerve; sl, spiral limbus; i, interdental cells; ihc, inner hair cells; p, pillar cells; ohc, outer hair cells; d, Deiter's cells; h, Hensen's cells; bm, basilar membrane; sp, spiral prominence; rm, Reissner's membrane. Reprinted with permission from Cohen-Salmon et al. (20) (© 1997 National Academy of Sciences, USA).

Hearing impairment is classified according to several critieria. The first criterion is the type of ear defect: conductive hearing loss, resulting from an outer or middle ear defect; sensorineural hearing loss, referring to a transmission anomaly of the sound signal from the inner ear to the cortical auditory centres of the brain (mostly due to cochlear defects); a mix of the two. The second criterion is the degree of severity of the hearing loss for the better hearing ear: mild hearing impairment corresponds to a loss of 27-40 dB; moderate 41-55 dB; moderate severe 56-70 dB; severe 71-90 dB; profound corresponds to a hearing loss >90 dB. The third criterion is the age of onset and progressiveness of the impairment. The last criterion for the classification of hearing impairment is whether it is associated with other symptoms (syndromic) or whether it is the sole defect (non-syndromic or isolated).

SYNDROMIC HEARING LOSS

It has been estimated that 30% of prelingual deafness cases are syndromic. Several hundred such syndromes, consisting of hearing loss in association with a variety of anomalies (such as eye, musculo-skeletal, renal, nervous and pigmentary disorders) have been described (4). Syndromic hearing loss can have many modes of transmission, including maternal inheritance due to a mitochondrial mutation. The forms may be conductive, sensorineural or mixed defects. Table 1 lists the genes and encoded molecules identified as underlying some of these syndromic forms. Two recently isolated genes deserve to be highlighted, as they underlie frequent forms of hearing loss and encode two newly identified proteins. The first of these two genes underlies Pendred syndrome. The encoded protein, Pendrin, is a putative sulphate transporter (5). The second underlies the less frequent Branchial-Oto-Renal (BOR) syndrome (6). The encoded protein, EYA1, is a transcriptional co-activator (7). There exist numerous examples of syndromic forms of deafness where the causative gene has not yet been cloned, but these forms represent the less prevalent syndromes.

Table 1. Molecules encoded by genes underlying syndromic forms of deafness
Category Gene Encoded molecule Syndrome Localization References
Extracellular matrix components COL4A3, -A4, Type IV ([alpha]3, [alpha]4) collagen Alport, autosomal recessive 2q35-37 23
COL4A5, -A6 Type IV ([alpha]5, [alpha]6) collagen Alport, X-linked Xq22 24,25
COL2A1 Type II ([alpha]1) collagen Stickler 12q13.1-13.3 26
KAL Anosmin-1 X-linked Kallmann's Xp22.3 27
NDP Norrin Norrie Xp11.3 28
Enzymes IDUA [alpha]-L-iduronidase Hurler 4q16.3 29
IDS Iduronate-2-sulfatase Hunter Xq27.3 30
ERCC3 Helicase Cockayne's 2q21 31
Factors belonging to transcriptional complexes PAX3 PAX3 Waardenburg type 1/3 2q36 31,33
MITF MITF Waardenburg type 2 3p12.3-14.1 34
SOX10 SOX10 Waardenburg-Hirschsprung 22q13 35
EYA1 EYA1 Branchio-Oto-Renal 8q13.3 6
SALLI SALLI Townes-Brocks 16q21.1 36
Cytoskeletal components NF2 Merlin Neurofibromatosis type II 22q12 37
MYO7A Myosin VIIA Usher type IB 11q13.5 38
Membrane components
Two molecules forming a functional ionic channel KvLQT1 KvLQT1 Jervell and Lange-Nielsen 11p15.5 39
KCNE1/IsK minK/IsK Jervell and Lange-Nielsen   40
Receptors plus their ligands FGFR2 Fibroblast growth factor receptor 2 Crouzon 10q25-26 41
EDNRB Endothelin-B receptor Waardenburg-Hirschsprung 13q22 42,43
EDN3 Endothelin 3 Waardenburg-Hirschsprung 22q13.2-13.3 44,45
A putative sulphate transporter PDS Pendrin Pendred 7q31 5
A putative nucleolar phosphoprotein TCOF1 Treacle Treacher-Collins 5q32-33.1 46
Mitochondrial genes tRNAleu(UUR) transfer RNAleu(UUR) NIDDMa, MELASa Mitochondrial 47
tRNAlys transfer RNAlys MERRF, MERRF/MELASa Mitochondrial 48,49
Only the causative genes for which the type of encoded molecule has been identified are presented here.
aNIDDM, non-insulin-dependent (type II) diabetes; MERRF, myoclonus epilepsy with ragged-red fibres; MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. NIDDM, MERRF and MERRF/MELAS are all associated with sensorineural deafness.

NON-SYNDROMIC HEARING LOSS

The non-syndromic forms of hearing loss are collectively referred to as DFN for the X-linked forms, DFNA for the autosomal dominant forms and DFNB for the autosomal recessive forms. Among the prelingual forms, DNFB account for ~85% of the cases, DFNA for 15% and DFN for 1-3%. Maternally inherited hearing loss due to a mitochondrial mutation, with or without an autosomal recessive mutation, have also been described (7-10). The autosomal recessive forms of hearing loss are often the most severe and account for the vast majority of cases of congenital profound deafness. These forms are almost exclusively sensorineural, due to cochlear defects. The mode of inheritance of postlingual forms of non-syndromic hearing loss manifesting before adulthood has not been extensively studied. However, as more pedigrees are described, the postlingual forms seem to be either autosomal dominant or maternally inherited due to mitochondrial mutations. The autosomal recessive forms are rare. Postlingual forms also seem to be mainly sensorineural defects and are often progressive. Among the late onset forms, which appear in young adulthood, otosclerosis is the most common cause of hearing impairment (0.2-1% of the adult population). This disorder has an autosomal dominant mode of transmission with incomplete penetrance. It is characterized, histologically, by isolated endochondral bone sclerosis of the bony labyrinth. Otosclerotic foci invade the oval window, interfering with free motion of the stapes and resulting in conductive hearing loss. A sensorineural component has also been documented, which may be due to the otosclerotic foci spreading inwards towards the cochlea.

To date, 20 DFNB, 14 DFNA and 4 DFN loci have been mapped. However, on occasion, more than one locus has been assigned to the same chromosomal region, suggesting that the same locus may have been given two names. Moreover, recessive and dominant forms have also been linked to the same chromosomal region, implying that the same gene could underlie both disorders. This has already been shown to be the case for the forms DFNB2 (11,12) and DFNA11 (13), as well as for DFNB1 (14) and DFNA3 (15). To date, taking into account that two deafness loci mapping to the same region could be due to a single gene defect, the minimum number of non-syndromic deafness loci identified is 36. However, these known loci do not account for all of the families studied to date, indicating that there still remain a significant number of unidentified loci underlying isolated forms of hearing loss. Finally, although the late onset disorder otosclerosis is thought to be genetically heterogeneous, the first locus to be linked to the defect was recently mapped to 15q25-q26 (16).

Table 2. Molecules encoded by genes underlying non-syndromic forms of deafness
Category Gene Encoded molecule Form Type of defect Localization Reference
Extracellular matrix components TECTA [alpha]-Tectorin DFNA8/12 Prelingual;
sensorineural		 11q22-24 22
Transcription factors POU3F4 POU3F4 DFN3 Prelingual;
progressive;
mixed		 Xq21.1 50
POU4F3 POU4F3 DFNA15 Postlingual;
progressive;
sensorineural		 5q31 51
Cytoskeletal components MYO7A Myosin VIIA DFNB2 Prelingual;
sensorineural		 11q13.5 11,12
DFNA11 Postlingual;
progressive;
sensorineural		 11q13.5 13
MYO15 Myosin XV DFNB3 Prelingual;
sensorineural		 17p11.2 52
diaphanous Diaphanous 1 DFNA1 Postlingual;
progressive;
sensorineural		 5q31 53
Cx26 Connexin26 DFNB1 Prelingual;
sensorineural		 13q11-12 14
DFNA3 Prelingual;
progressive;
sensorineural		 13q12 15
Membrane components PDS Pendrin DFNB4 Prelingual;
sensorineural		 7q31 54
Mitochondrial genes 12s rRNA 12S rRNA MINSDa Postlingual;
progressive;
sensorineural		 Mitochondrial 8
tRNAser(UCN) tRNA ser(UCN) MINSDa Postlingual;
progressive;
sensorineural		 Mitochondrial 9
aMINSD, maternally inherited non-syndromic deafness.

The difficulties encountered in linkage analysis and cloning of the genes responsible for non-syndromic hearing loss have been extensively discussed elsewhere (17). A large number of these difficulties have now been circumvented by linkage analysis of carefully selected families (18). The particular requirements of linkage studies are such that, in most instances, they result in the definition of a large and unmanageable candidate gene interval. In such cases, the candidate gene approach is the most appropriate cloning strategy. However, this approach itself presents many difficulties, due to the paucity of molecular data concerning the development of the inner ear and auditory function. Such a situation exists due to the great variety of cochlear cells and because each of these groups of cells is present in small numbers. Amongst the putative candidate genes, those which are prefentially (19) or specifically (20) expressed in the inner ear can now be effectively isolated by PCR-based cDNA substraction techniques. The power of this approach has been largely demonstrated by its application to the isolation of genes responsible for retinal deficiencies (21) and has recently found its first application in isolated forms of deafness. The gene encoding [alpha]-tectorin, a major component of the tectorial membrane and the first cochlear specific-component to be identified (using a biochemical approach), has been demonstrated to underlie an autosomal dominant form of deafness (DFNA8/12) (22). Today, a total of 10 genes have been cloned and shown to underlie non-syndromic hearing loss (see Table 2). The first gene to be identified was the mitochondrial gene 12S rRNA (8). Interestingly, it has only been in the last 2 years that the remaining genes were cloned, illustrating the recent boom in interest and progress in this subject.

INSIGHTS INTO THE DEVELOPMENT AND PHYSIOLOGY OF THE EAR

Studies of the molecular basis of hearing loss bring to light the genes encoding proteins for which no functional redundancy exists in the ear. As shown in Tables 1 and 2, the genes underlying syndromic and non-syndromic forms of deafness encode a large diversity of molecules, including extracellular matrix components, enzymes, factors belonging to transcriptional complexes, cytoskeletal components and membrane components, as well as four different mitochondrial encoded proteins, three tRNA molecules and one rRNA molecule. In most instances, in itself, the identification of a deafness gene provides limited information. It allows an entry point into the corresponding developmental or physiological processes, beyond which, however, there still remains a world of understanding. Specific difficulties are encountered in understanding the role of each of these molecules. The ease with which these difficulties can be addressed depends on the amount of information already available concerning related molecules and the developmental/differentiation processes in which the molecule is involved, as well as the availability of an animal model, usually a mouse model. Below we will discuss the major progress achieved during the last years in understanding the pathogenesis of syndromic and non-syndromic deafness. This concerns the auditory-pigmentary diseases, Jervell and Lange-Nielsen syndrome and, to a lesser extent, the isolated forms of deafness DFNB1/DFNA3 and BOR syndrome, as well as Usher 1B syndrome (and the isolated forms of deafness DFNB2/DFNA11).

Most of the melanocytes of the body are derived from neural crest cells which migrate out of the neural tube, through the mesenchyme of the developing embryo to specific target sites, including skin, hair follicles and inner ear, where they differentiate and begin to synthesize melanin. Mutations in the genes encoding proteins involved in the development, differentiation or survival of neural crest cells and their melanoblast derivatives and in the melanogenesis process can result in a hypopigmentary disorder (for a review see ref. 55). A fraction of the numerous pigmentary diseases described are associated with deafness. The mutations so far identified in genes involved in formation of melanosomes or in synthesis of melanin do not lead to deafness, which is consistent with the normal hearing of albino animals. In contrast, mutations in certain genes involved in the earlier stages of neural crest cell development to the maturation of melanocytes do lead to deafness. Indeed, vestibular dark cells and cells of the cochlear stria vascularis (marginal and/or intermediate) are derived from the neural crest. It is accepted that the vestibular dark cells and the marginal cells of the stria vascularis are involved in secretion of potassium into the endolymph. When these cells are defective it leads to an abnormal endocochlear potential and thus hearing impairment. Included in the category of genes underlying auditory-pigmentary diseases are PAX3 (Waardenburg type 1 and 3), MITF (Waardenburg type 2), SOX10, EDNRB and EDN3 [Waardenburg-Hirschsprung disease, also called Waardenburg-Shah (WS4) syndrome]. Another two genes belonging to this category, encoding the receptor c-kit and its ligand steel, have been shown to be responsible for an auditory-pigmentary disease in mice, but have not been associated with an auditory defect in humans.

PAX3 is a transcription factor with two putative DNA binding domains (a paired box domain and a homeobox domain), an octapeptide domain and a putative transcription activation site (56). MITF belongs to the basic helix-loop-helix zipper family of transcription factors (57). In mice, MITF has been shown to bind to the melanocyte-specific enhancer element M box in the regulatory regions of two genes involved in melanin production, tyrosinase and TRP-1 (tyrosinase-related protein 1) (58). Moreover, it has recently been shown that PAX3 directly transactivates the MITF promoter (59). This is the first characterization of a cascade of transcription factors involved in the development/differentation of melanocyte precursors migrating from the neural tube to the developing ear. In the mouse, Pax3 has been shown to be expressed in the cephalic neural crest cells (56) and Mitf at the 25-26 somite stage in cells located between the otic vesicle and the neuroepithelium of the hindbrain (60). These cells are likely to represent migrating neural crest-derived melanocyte precursors that will eventually colonize the presumptive stria vascularis. Taken together, the above results suggest that Pax3 and Mitf play roles in the early development of neural crest-derived melanocytes. Moreover, Mitf has been shown to play a role in melanocyte differentiation (58,61) and, although no conclusive evidence is yet available of a role for Pax3, this gene is consistently expressed in the developing cochlea (62). Recently, mutations in the gene encoding another transcription factor, SOX10, were identified as underlying WS4 syndrome (35). SOX10 belongs to a family of proteins characterized by a domain which is similar to the high mobility group (HMG) DNA-binding motif present in the mammalian sex-determining protein SRY. SOX10 is expressed in migrating neural crest cells and in the otic vesicle (63). However, the actual developmental steps controlled by SOX10 still remain to be determined. Finally, mutations in both the endothelin-[Bgr] receptor (42,43) and its ligand endothelin-3 (44,45) have also been shown to underly WS4 syndrome. These receptor and ligand molecules have been proposed to be involved in an autocrine signal pathway necessary to maintain migration and tissue colonization by neural crest-derived melanocytes (64).

Two genes have been recognized as responsible for Jervell and Lange-Nielsen syndrome, a recessive disorder characterized by a severe bilateral deafness associated with cardiac arryhthmias with a prolonged QT interval on an electrocardiogram. The first of these is the potassium channel gene KvLQT1 (39), which encodes a pore-forming subunit with six transmembrane domains (65). The second encodes the potassium channel protein IsK (also called minK) (40), with a single transmembrane domain, which interacts with KvLQT1 to form a functional channel (66,67). In the inner ear, the Isk/KvLQT1 channel is present in vestibular dark cells (68) and in the marginal cells of the stria vascularis (39,69), where there is strong evidence suggesting a role for this channel in the secretion of potassium into the endolymph (70). Mutations in both KvLQT1 (71) and IsK (72,73) have also been shown to underlie the autosomal dominant disorder Romano-Ward (RW) syndrome, which is characterized by the aforementioned cardiac anomalies but without the association of deafness. Transfection experiments using COS cells (65) and Xenopus oocytes (74) have shown that KvLQT1 mutations giving rise to RW syndrome are dominant negative mutations which preserve partial function of the IsK/KvLQT1 channel. Accordingly, these results suggest that a residual function of this potassium channel is preserved in the inner ear of RW patients and may provide adequate potassium homeostasis in the cochlea.

The autosomal recessive and dominant forms of isolated deafness, DFNB1 and DFNA3, have been shown to arise from mutations in the gene Cx26 (also called GJB2), which encodes the gap junction protein connexin26 (14,15). DFNB1 results from a loss of function of both alleles, whereas DFNA3 is likely due to a dominant negative effect related to the homohexameric structure of this intercellular channel (15). Gap junctions are permeable to certain small molecules and ions, which are thus transferred between adjacent cells (75). In the inner ear, connexin26 is localized in the supporting cells within and flanking the organ of Corti, and in the fibrocytes of the spiral limbus and spiral ligament (Fig. 3). It has been postulated that on auditory stimulation, the K+ which has influxed into hair cells is released and recycled via the connexin26 channels. Hair cell K+ is thought to be recaptured by supporting cells and transferred via the fibrocytes to the interdental cells of the spiral limbus or to the marginal cells of the stria vascularis, whereupon it re-enters the endolymph (76,77). To test this hypothesis, an animal model is required which, to date, does not exist, given that the knock-out of this gene is lethal in mice due to placental anomalies (78).


Figure 3. Localization of connexin26 in the adult mouse inner ear. Immunohistofluorescence using a polyclonal antibody to connexin26 results in a strong signal in the inner sulcus and Claudius' cells on either side of the organ of Corti and in the fibrocytes of the spiral limbus (sl) and of the spiral ligament (SL). rm, Reissner's membrane; sg, spiral ganglion; sv, stria vascularis. Courtesy of A. El-Amraoui (Institut Pasteur, France).

BOR syndrome is an autosomal dominant disorder characterized by varying combinations of branchial, otic and renal anomalies indicative of an early developmental defect. Mutations in a human homologue (EYA1) of the Drosophila developmental gene eyes absent have been shown to underlie the syndrome (6). Two other human homologues of EYA1 have been identified, providing evidence for a novel gene family, which has also been characterized in the mouse (6,79,80). The EYA family members are composed of a highly conserved C-terminal region and a divergent N-terminal region (6). In mice, the N-terminal region has been shown to be a transactivator domain (7). Recent studies in Drosophila have shown that the conserved C-terminal region binds to a transcriptional co-activator, dachsund (81), and to the transcription factor sine oculis (82). Taken together, these results indicate that EYA1 is a transcriptional co-activator. The Drosophila eyes absent gene has been shown to direct eye specification and differentiation of photoreceptor cells (81,82). EYA1 is expressed in the branchial arches (which give rise to the outer and middle ear) and differentiating otic vesicle (the inner ear precursor), consistent with the outer, middle and inner ear anomalies of the syndrome (V. Kalatzis, manuscript in preparation). The proteins interacting with EYA1 during ear development and the particular role of EYA1 in inner ear developmental and differentiation pathways remain to be determined.

Usher IB syndrome is the most frequent form of Usher I syndrome, which is characterized by congential deafness associated with vestibular dysfunction and retinitis pigmentosa appearing before puberty. This autosomal recessive disorder is caused by mutations in the MYO7A gene encoding an unconventional myosin, myosin VIIA (38). Moreover, the isolated forms of deafness DFNB2 (11,12) and DFNA11 (13) are also caused by mutations in MYO7A. DFNA11 is likely to be due to mutations exerting a dominant negative effect as a result of the homodimerization of the tail of this protein (12). In the inner ear, MYO7A is expressed as early as E10 (83) and its expression is subsequently restricted to the sensory cells (84,85). Myosin VIIA is localized in the growing and mature stereocilia of hair cells (84,85). It is particularly concentrated around the cuticular plate in which the roots of the stereocilia are anchored (86), although not exclusively localized to this region. The existence of a variety of mouse mutants carrying mutations in Myo7A, the shaker-1 mutants (87,88), has already proved to be a useful start for our understanding of inner ear physiological processes which are impaired as a result of defects in this gene. Studies of some of these mice have shown that myosin VIIA is involved in the organization of the hair cell stereociliary bundles (89). Moreover, this protein is also involved in hair cell trafficking of aminoglycosides, which are known to induce ototoxicity (90). However, the precise role that myosin VIIA plays in each of these processes still remains to be determined.

MEDICAL IMPACT OF DEAFNESS RESEARCH

The recognition of various isolated forms of deafness by their genetic basis should lead to their clinical characterization. This in turn should allow division of the vast collection of these sensorineural defects into several nosological entities. Included in such a characterization should be information on the age of onset, the degree of severity, the shape of the audiometric curves, the progressiveness of the disorder and the putative inter- and intra-familial phenotypic variations. In addition, information concerning the possible association of vestibular dysfunction as well as the presence/absence of cochlear anomalies, detectable by computerized tomography, should also be available. Finally, for the autosomal recessive forms data concerning a putative a minima hearing defect in carrier individuals should be included.

To date, the bulk of the clinical information available concerns the autosomal dominant forms of hearing loss, as most of the studied families live in developed countries. In contrast, few data have accumulated concerning the autosomal recessive forms, as the highly consanguineous families studied mainly live in underdeveloped countries. In the most favourable situations, a detailed clinical description of a few families selected for linkage analysis is provided. However, this description remains fairly limited and a larger number of families needs to be analysed in order to obtain a reliable clinical description. The paucity of such data is regrettable, as a detailed clinical description is a prerequisite for guiding the future search for mutations in the corresponding gene and for subsequently providing accurate genetic counselling. Along the same lines, current epidemiological data concerning hereditary forms of deafness are scarce.

Nevertheless, major advances in the medical field have recently surfaced which allow the rapid determination of the genetic origin of deafness in a large number of cases. This stems from the identification of two genes which frequently underlie non-syndromic forms of deafness, despite the extreme genetic heterogeneity of these forms. Firstly, the Cx26 gene, which contains a single coding exon, thus making the search for mutations facile, was shown to account for up to 50% of all cases of prelingual, autosomal recessive hereditary hearing loss (91,92). Moreover, one particular Cx26 mutation (which may be related to a mutation hot-spot), called either 30delG (91) or 35delG (92), represents ~70% of all Cx26 mutations. These data are derived from studies performed mainly on populations from France, Spain, Italy, the UK, New Zealand and Tunisia (91-93); there is a noticeable absence of data from the Americas, Africa and Asia. Due to the high prevalence of Cx26 mutations, genetic counselling of the deaf is perhaps the most beneficial outcome of deafness research. In contrast to other sensory defects, such as retinal deficiencies, environmental causes frequently underlie forms of deafness and are thought to be overlooked in numerous situations. Thus, when confronted with a single case of isolated deafness within a family asking for the risk of recurrence of the defect, only molecular diagnosis could affirm a genetic origin. The discovery that mutations in Cx26 underlie a huge proportion of isolated forms of deafness is a considerable aid in genetic counselling, as a genetic origin can now be quickly established in families with a single affected child. Medical geneticists now need to be prepared to respond to possible requests for prenatal diagnosis. The ensuing ethical discussion should take into consideration, on the one hand, the quality of life that deaf children can have with adequate education and hearing aids or cochlear implants (see below) and, on the other hand, the severity of the hearing defect. Unfortunately, though, the inner ear defects arising from Cx26 mutations have not yet been characterized fully.

Secondly, a mutation in the mitochondrial 12S rRNA gene, A1555G, was shown to underlie both an isolated form of sensorineural deafness (9,10) and deafness induced by aminoglycoside treatment (94,95), and to occur rather frequently. Again, the bulk of the data available concerning A1555G has been derived from a European population, namely Spanish (95). Assuming that this mutation is also frequent in other populations, the discovery that A1555G predisposes one to deafness arising from aminoglycoside treatment should find immediate medical application in the prevention of future use of these antibiotics. This work emphasizes the importance of a thorough investigation of the clinical history of all family members of a child who is a candidate for aminoglycoside treatment. The particularly simple search for this mutation should be generally performed and, moreover, systematically employed when there is the slightest suspicion of hearing impairment within a family or, a fortiori, in the child in question.

So far, this research has yet to result in the development of new treatments. The treatments available, to date, are the amplification of sound (using hearing aids) or stimulation of the cochlear nerve or nucleus via cochlear or auditory brainstem implants respectively. We now know, from isolation of some of the causative deafness genes, that diverse developmental, physiological and cellular anomalies are at the origin of hereditary hearing loss. Consequently, the development of new treatments will only be possible when a minimum amount of knowledge concerning each of these defective processes has been accumulated. Parallel efforts to induce regeneration of inner ear sensory cells (96,97) and to introduce replacement genes via viral vectors (98) will soon become the most exciting avenues leading to possible treatment of hearing impairment, regardless of whether the origin of the defect is genetic or environmental.

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*To whom correspondance should be addressed. Tel: +33 1 45 68 88 50/88 90; Fax: +33 1 45 67 69 78; Email: cpetit@pasteur.fr

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