Учебники / Genetics and Auditory Disorders Keats 2002

which provides information to the brain about head movement. Otolithic membranes lie over the saccular and utricular maculae. They contain small, calcium-rich, crystalline structures called otoliths, which make the otolithic membrane denser than the surrounding endolymph. The gravitational force on the otoliths provides information to the brain about head position. These extracellular membranes are secreted by the underlying epithelium, most likely by the supporting cells.

Several of the mutants described have abnormal otolithic membranes, either small or undetectable, or containing giant otoliths. The defects can be variable among mutants, and can be unilateral (Lim et al. 1978; Trune and Lim 1983a,b). The genes so far identified encode calcium channels and pumps (Slc30a4; Atp2b2), a component of the intracellular secretory pathway (Ap3d), and an extracellular matrix molecule (Otog) that appears to be required to attach the membrane to the underlying epithelium. Defective otolithic membranes have been described in mutations of two transcription factors (Atf2 and Msx2). Such defects may be secondary to gross inner ear malformations, and there are probably many examples of inner ear malformations with otolithic or cupular defects that are not specifically described in the literature. Mutants with specific otolithic or cupular membrane defects do not necessarily have impaired cochlear function, and no humans with mutations in the same genes have been described yet.

The tectorial membrane is the extracellular matrix of the cochlea, and is secreted by the supporting cells of the organ of Corti as well as the cells of Kölliker’s organ during development. Kölliker’s organ later regresses to form the inner spiral sulcus. Abnormalities of the tectorial membrane have been described in many different deaf mouse mutants. However, the structure is notoriously susceptible to histological artefact during preparation, and when underlying hair cells degenerate,it loses some of its attachment points,so care must be taken in interpreting these observations, since they may not involve a primary tectorial membrane defect. However, recently four different mutants have been described that do seem likely to involve primary tectorial membrane defects and associated hearing impairment. The Col11a2 knockout and the Otog knock-out mutations have both been described with subtle ultrastructural anomalies of the tectorial membrane, suggesting that the molecules encoded by these genes are probably components of this membrane (Simmler et al. 2000; McGuirt et al. 1999). A targetted mutation of Tecta, in contrast, leads to major ultrastructural abnormalities of the tectorial membrane, which is not surprising because the a-tectorin molecule encoded by

Tecta was identified previously as a major component of the membrane

(Legan et al. 2000). Lastly, double mutants for two thyroid hormone receptors, Thra and Thrb, show more severely elevated thresholds than the Thrb- deficient single mutant, and preliminary analysis indicates the presence of some malformation of the tectorial membrane in the double mutant (M

Kelley and D Forrest, personal communication 2000).

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Two of these tectorial membrane genes are known to be involved in human hereditary deafness; they are COL11A2 and TECTA. TECTA is mutated in some forms of both dominant and recessive nonsyndromic deafness (DFNA8/12 and DFNB21), while COL11A2 underlies the nonsyndromic DFNA13 as well as syndromic deafness in Stickler/OSMED syndrome (Griffith and Friedman, Chapter 6). It seems likely that tectorial membrane abnormalities underlie the hearing impairment seen in these forms of human deafness. People with mutations of the thyroid hormone receptor THRB show resistance to thyroid hormone and often have associated hearing impairment (Brucker-Davis et al. 1996; Refetoff et al. 1967). It is not clear whether these people are hearing-impaired because of a tectorial membrane defect, or because of some other cochlear defect resulting from delayed development.

2.6 Neural Defects

There is an increasing number of mouse mutants reported to have specific defects in the peripheral or central auditory pathways (Tables 8.6 and 8.7). One group of molecules, the neurotrophins and their receptors, appears to be essential for the survival of inner ear neurons during development. Both cochlear and vestibular afferent neurons arise from cells that delaminate from the early otic vesicle, migrate from the epithelium to form the cochleovestibular ganglion, extending dendrites back towards sensory hair cells in the inner ear and axons that connect with the central auditory and vestibular nuclei. Mice with knockouts of the brain-derived neurotrophic factor gene (Bdnf ), or its receptor (Ntrk2), have no surviving afferent innervation of the cristae of the semicircular canals and a much reduced afferent supply to the maculae and to cochlear outer hair cells. In contrast, in mice with the neurotrophin-3 gene (Ntf3) or the corresponding receptor gene (Ntrk3) disrupted, the afferent innervation of the cochlea is severely reduced and there is minor loss of vestibular neurons. In mice that have both receptors (Ntrk2 and Ntrk3) or both neurotrophins (Bdnf and Ntrk3) inactivated, there is a complete loss of afferent innervation to the inner ear. The effects of these mutations have been reviewed in some detail recently (Fritzsch et al. 1997b, 1999b and Table 8.6 for references).

Other mutations can lead to abnormal development of the inner ear ganglia. Mutations in Pou4f1 or Ap2 lead to reduced or abnormal cochleovestibular ganglia (McEvilly et al. 1996; Zhang et al. 1996; Schorle et al. 1996), and knock-out of the neurogenin1 gene, ngn1, causes a complete absence of all afferent, efferent and autonomic innervation of the inner ear (Ma et al. 1998; Fritzsch et al. 1999a).

Efferent fibres arise from the neural tube in the hindbrain region, and the autonomic innervation of the inner ear originates in the superior cervical ganglion, a neural crest derivative (Fritzsch et al. 1997b). There are several mutants that affect the development of the efferent system. The

The table includes the major genes or loci known to be involved in deafness and/or balance defects. Only the key references describing the ear phenotype and the initial identification of the gene are included, so the list is not intended to be comprehensive. The chromosomal localization is given where this is known, with the distance in cM from the centromere given in parentheses. KO, Knock-out. NK, Not known. Under Inheritance column: R, Recessive; D, Dominant; SD, Semidominant; E, Epistatic; M, Maternal effect. Under Origin column: R, Radiation-induced; S, Spontaneous; T, Transgenics and knockouts; C, Chemical mutagenesis; I, Transgenic Insertional mutations.

References: 1, Martini et al. 1995; 2, Pata et al. 1999; 3, Nishi et al. 1997; 4, Bianchi et al. 1996; 5, Ernfors et al. 1994; 6, Ernfors et al. 1995; 7, Jones et al. 1994; 8, Schorle et al. 1996; 9, Zhang et al. 1996; 10, Vetter et al. 1999; 11, Chisaka et al. 1992; 12, Gavalas et al. 1998; 13, Lufkin et al. 1991; 14, Mark et al. 1993; 15, Rossel and Cappechi 1999; 16, Fariñas et al. 1994; 17, Fritzsch et al. 1997a; 18, Fritzsch et al. 1995; 19, Minichiello et al. 1995; 20, Schimmang et al. 1995; 21, Adlkofer et al. 1995; 22, Suter et al. 1992; 23, Wang et al. 1995; 24, Zhou et al. 1994; 25, Ma et al. 1998; 26, Fritzsch et al. 1999a; 27, McEvilly et al. 1996; 28, Rio et al. 1999.

contralateral efferent supply to the inner ear arises from rhombomere 4 of the developing hindbrain, and this projection across the midline is abnormal or absent in Hoxb1 or Gata3 mutants (Studer et al. 1996; Pata et al. 1999). The nicotinic acetyl choline receptor a9 subunit is normally expressed in sensory hair cells, and in mice with mutations of this gene the

274 K.P. Steel et al.

pattern of synapses is altered on outer hair cells, with a single large terminal instead of many small endings on each hair cell (Vetter et al. 1999). The efferent supply of outer hair cells is believed to permit suppression of cochlear responses, and this physiological feature is absent in the a9 mutants (Vetter et al. 1999).

Several neurological mutants show specific defects of cell types within the central auditory pathways. The nervous, lurcher, Purkinje cell degeneration, and staggerer mutants all have specific cartwheel cell defects in the dorsal cochlear nucleus, and in reeler mutants the dorsal cochlear nucleus is disorganized with reduced numbers of granule cells (Berrebi and Mugnaini 1988; Berrebi et al. 1990; Martin 1981).

TABLE 8.7. Mouse mutants with central auditory system defects

The table includes the major genes or loci known to be involved in deafness and/or balance defects. Only the key references describing the ear phenotype and the initial identification of the gene are included, so the list is not intended to be comprehensive. The chromosomal localization is given where this is known, with the distance in cM from the centromere given in parentheses. KO, Knock-out. NK, Not known. Under Inheritance column: R, Recessive; D, Dominant; SD, Semidominant; E, Epistatic; M, Maternal effect. Under Origin column: R, Radiation-induced; S, Spontaneous; T, Transgenics and knockouts; C, Chemical mutagenesis; I, Transgenic Insertional mutations.

References: 1, Pata et al. 1999; 2, Michaelson et al. 1996; 3, Propst et al. 1990; 4, Rauch 1992; 5, Reimer et al. 1996; 6, Urbánek et al. 1994; 7, D’Arcangelo et al. 1995; 8, Hirotsune et al. 1995; 9, Martin 1981; 10, Chisaka et al. 1992; 11, Gavalas et al. 1998; 12, Lufkin et al. 1991; 13, Mark et al. 1993; 14, Rossel and Cappechi 1999; 15, Berrebi et al. 1990; 16, Zuo et al. 1997; 17, Kosel et al. 1998; 18, Street et al. 1998; 19, Takahashi and Kitamura 1999; 20, Bock et al. 1983; 21, Deol et al. 1983; 22, Horner and Bock 1985; 23, Horner et al. 1985; 24, Conlee et al. 1991; 25, Creel et al. 1983; 26, Moore et al. 1988; 27, Berrebi and Mugnaini 1988; 28, Mathews et al. 1995; 29, Hamilton et al. 1996; 30, Wehr et al. 1997; 31, Acampora et al. 1996; 32, Acampora et al. 1998; 33, Acampora et al. 1999; 34, Morsli et al. 1999; 35, Adlkofer et al. 1995; 36, Suter et al. 1992; 37, Zhou et al. 1994; 38, Gavalas et al. 1998; 39, Goddard et al. 1996; 40, Rossel and Cappechi 1999; 41, Studer et al. 1996; 42, Bertoni et al. 1993; 43, O’Malley et al. 1995; 44, Stein et al. 1994; 45, Harman et al. 1954; 46, Acampora et al. 1995; 47, Matsuo et al. 1995; 48, Gogos et al. 1999; 49, Ebersole et al. 1996; 50, Shah and Salamy 1980; 51, Sidman et al. 1964; 52, Fujiyoshi et al. 1994; 53, Meyers et al. 1998; 54, Nishi et al. 1997.

Other mutants have been reported to have a reduced or absent inferior colliculus (Fkh5, Wehr et al. 1997; Fgf8, Meyers et al. 1998; Otx2, Matsuo et al. 1995; Pax5, Urbánek et al. 1994), or an enlarged inferior colliculus, as in Otx1 mutants (Acampora et al. 1996). This does not necessarily correlate with abnormal gross function (Reimer et al. 1996), although detailed analyses have not yet been carried out in any of these mutants. Prolonged interpeak intervals of brainstem-evoked potentials suggesting abnormal central auditory system function have been reported in the myodystrophy (myd, Mathews et al. 1995), shiverer (Mbp, Fujiyoshi et al. 1994), quaking (qkI, Shah and Salamy 1980) and osteopetrosis (Csf1, Michaelson et al. 1996) mutants, but the structural basis of these functional defects is not known. The quivering mutant has normal gross auditory-system anatomy,

276 K.P. Steel et al.

and normal cochlear response thresholds, but thresholds are raised when measured from central nuclei, suggesting a defect of central origin (Bock et al. 1983; Horner and Bock 1985).

Lastly, two mutants show specific central auditory-system dysfunction. The nociceptin-receptor knock-out mouse shows normal thresholds, but an impaired ability to recover from intense sound exposure. The expression of this receptor molecule around the crossed olivocochlear bundle, which supplies the contralateral efferent neurons to the cochlear hair cells, suggests the receptor may act by modulating efferent activity (Nishi et al. 1997). Proline dehydrogenase (Prodh) mutants also show normal thresholds, but attenuated pre-pulse inhibition, a phenomenon whereby the behavioural response to a sound is moderated by prior exposure to a pre-pulse. This observation suggests a defect in central processes of sensorimotor gating (Gogos et al. 1999).

It is very likely that many other mouse mutants, particularly those with generalized neurological defects, will be shown to have specific auditory system anomalies, but most of them have not yet been analysed in any detail. Central auditory system anomalies are highly likely to be found in any cases of peripheral hearing impairment because of the importance of normal sensory input to refining the neural circuitry of the brain during development. However, specific central auditory system defects are relatively rare in humans, and there are no clear examples wherein comparison with any of the mouse models described above is possible. However, pre-pulse inhibition has been described as a feature of schizophrenia, so any mouse mutants showing this feature may be of particular interest to psychiatric research.

3. Summary

There is now a large number of mouse mutants with hearing and/or balance defects available for investigating the reasons for the impairment, and these mutants will all contribute to our growing understanding of the complexity of deafness. Many more mouse mutants are candidates for involvement of the auditory system, but their hearing has not yet been investigated in any detail. Some of these are listed in additional tables available at the Web site accompanying this chapter (Steel 2000). However, comparison of the chromosomal locations of these mutations causing deafness in the mouse with the locations of known human deafness mutations reveals that there are many human loci for which no mouse model has yet been discovered. Two major mutagenesis programs are ongoing in Europe, at Neuherberg, Germany and Harwell, UK, and new deaf mouse mutants are being isolated from these screens to help to fill the gap between human deafness and mouse models (Nolan et al. 2000). Large-scale, genome-wide mutagenesis programmes are starting in other countries too, including the

US, so there will soon be many more mutants available. Deafness is one of the most heterogeneous diseases known in humans, and study of the many deaf mouse mutants will help unravel the molecular basis of the pathology, an essential first step towards a rational approach to treatment.

Acknowledgments. This work was supported by the UK Medical Research Council, the European Commission, and Defeating Deafness. We thank the people who have kindly allowed us to include their data prior to publication, including Drs. Ken Johnson, Yin Zheng, Verity Letts, Wayne Frankel, Jo Cable, Rachel Hardisty, Matthew Kelley, Douglas Forrest and David Beier, and Donna Fekete for kind permission to reprint Figure 8.1.

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