Учебники / Genetics and Auditory Disorders Keats 2002

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TABLE 8.1. Continued

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, Knockout. 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, Juriloff et al. 1985; 2, Zoltewitz et al. 1999; 3, Johnson et al. 1999; 4, Xu et al. 1999; 5, Mo et al. 1997; 6, ten Berge et al. 1998; 7, Juriloff et al. 1992; 8, McLeod et al. 1980; 9, Qui et al. 1997; 10, Schorle et al. 1996; 11, Zhang et al. 1996; 12, Lyon et al. 1996; 13, Curry 1959; 14, Arikawa-Hirasawa et al. 1999; 15, Satokata and Maas 1994; 16, Acampora et al. 1999b; 17, Depew et al. 1999; 18, Chisaka et al. 1992; 19, Gavalas et al. 1998; 20, Lufkin et al. 1991; 21, Mark et al. 1993; 22, Rossel and Cappechi 1999; 23, Gendron-Maguire et al. 1993; 24, Mallo 1997; 25, Mallo and Gridley 1996; 26, Rijli et al. 1993; 27, Hardisty et al., in preparation; 28, Kingsley et al. 1992; 29, J. Cable and Steel, in preparation; 30, Honarpour et al. 2000; 31, Naora et al. 1994; 32, Gavalas et al. 1998; 33, Goddard et al. 1996; 34, Rossel and Cappechi 1999; 35, Studer et al. 1996; 36, Barrow and Cappechi 1996; 37, Altschuler et al. 1991; 38, Bohne and Harding 1997; 39, Bonadio et al. 1990; 40, Dupé et al. 1999; 41, Ghyselinck et al. 1997; 42, Lohnes et al. 1994; 43, Peters et al. 1998; 44, Rivera-Pérez et al. 1995; 45, Yamada et al. 1995; 46, Zhu et al. 1997; 47, Kurihara et al. 1994; 48, Winograd et al. 1997; 49, Watanabe and Yamada 1999; 50, Acampora et al. 1999a; 51, Matsuo et al. 1995; 52, Morsli et al. 1999; 53, Minowa et al. 1999; 54, Phippard et al. 1999; 55 Phippard et al. 2000; 56, Theiler and Sweet 1986; 57, Clouthier et al. 1998; 58, Yanagisawa et al. 1998; 59, Martin et al. 1995; 60, Yang et al. 2000.

the gene, and a radiation-induced deletion of a similar upstream region has been found in the sex-linked fidget mouse mutant (de Kok et al. 1995; Phippard et al. 2000). Finally, the p73 knockout recently reported is the first to show a single gene mutation conferring a predisposition to middle ear inflammation, and this is mediated by the gene’s involvement in the immune system (Yang et al. 2000). Since otitis media in children can be a serious clinical problem, the finding of a single gene predisposing to middle ear

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inflammation suggests a candidate gene that could be investigated for changes in children most severely affected.

2.2 Inner Ear Malformations

Gross malformations (morphogenetic defects) of the inner ear occur in many different mutants, as listed in Table 8.2. Many of these show semicircular canal defects, such as truncations of one or more of the canals (Fig.

8.2), and the preponderance of these may reflect ascertainment bias because they are relatively easy to detect. However, defects can range from a tendency for a single canal to be thin or truncated (Fig. 8.2B), to an extreme failure of the otic vesicle to develop into anything more than an elongated

TABLE 8.2. Mouse mutants with inner ear malformations

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TABLE 8.2. Continued

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, Crenshaw et al. 1991; 2, Abdelhak et al. 1997; 3, Johnson et al. 1999; 4, Xu et al. 1999; 5, Deol 1966a; 6, Epstein et al. 1991; 7, Fleming et al. 1996; 8, Goulding et al. 1993; 9, Steel and Smith 1992; 10, Deol 1964a; 11, Millonig et al. 2000; 12, Wilson 1985; 13, Wilson and Wyatt 1995; 14, ten Berge et al. 1998; 15, Truslove 1956; 16, Qiu et al. 1997; 17, Cordes and Barsh 1994; 18, Deol 1964b; 19, Eichman et al. 1997; 20, Frohman et al. 1993; 21, McKay et al. 1994; 22, McKay et al. 1996; 23, Ruben 1973; 24, Schorle et al. 1996; 25, Zhang et al. 1996; 26, Nolan et al. 1995; 27, Bohne and Harding 1997; 28, Propst et al. 1990; 29, Rauch 1992; 30, Deol 1976; 31, Deol 1980; 32, Deol 1983; 33, Khaze’I 1974; 34, Lyon et al. 1996; 35, Acampora et al. 1999b; 36, Depew et al. 1999; 37, Chisaka et al. 1992; 38, Gavalas et al. 1998; 39, Lufkin et al. 1991; 40, Mark et al. 1993; 41, Rossel and Cappechi 1999; 42, Gendron-Maguire et al. 1993; 43, Mallo 1997; 44, Mallo and Gridley 1996; 45, Rijli et al. 1993; 46, Deol 1974; 47, Van Abeelen and Van Der Kroon 1967; 48, De Moerlooze et al. 2000; 49, Hadrys et al. 1998; 50, Wang et al. 1998; 51, Chan et al. 2000; 52, Hardisty et al., in preparation; 53, Mansour et al. 1993; 54, Honarpour et al. 2000; 55, Kacser et al. 1979; 56, Taylor et al. 1993; 57, Acampora et al. 1996; 58, Acampora et al. 1998; 59, Acampora et al. 1999a; 60, Morsli et al. 1999; 61, Henkemeyer et al. 1995; 62, Altschuler et al. 1991; 63, Bonadio et al. 1990; 64, Gavalas et al. 1998; 65, Goddard et al. 1996; 66, Rossel and Cappechi 1999; 67, Studer et al. 1996; 68, Dupé et al. 1999; 69, Ghyselinck et al. 1997; 70, Lohnes et al. 1994; 71, Hui and Joiner 1993; 72, Johnson 1967; 73, Teng et al. 2000; 74, Matsuo et al. 1995; 75, Berggren et al. 1997; 76, Pace et al. 1997; 77, Van De Water and Galinovic-Schwartz 1987; 78, Vetter et al. 1996; 79, Letts et al. 2000; 80, Deol 1966b; 81, Zeng et al. 1997; 82, Lyon 1958; 83, Ting et al. 1994; 84, Delpire et al. 1999; 85, Deol 1963; 86, Deol 1968; 87, Dixon et al. 1999; 88, Flagella et al. 1999; 89, Johnson et al. 1998; 90, Deol and Lane 1966; 91, Wenngren and Anniko 1988; 92, Wenngren and Anniko 1990; 93, Favor et al. 1996; 94, Keller et al. 1994; 95, Torres et al. 1996; 96, Minowa et al. 1999; 97, Phippard et al. 1999; 98, Phippard et al. 2000; 99, McNutt 1968; 100, Deol and Dickie 1967; 101, Lyon 1960; 102, Deol 1980; 103, Bonnevie 1936; 104, Deol 1976; 105, Stein and Huber 1960; 106, Salminen et al. 2000; 107, Niederreither et al. 2000; 108, Martin et al. 1995; 109, Hulander et al. 1998.

cyst (Fig. 8.2D). Auditory function may be undetectable in some of these mutants, or may be normal in mutants with only minor vestibular malformations, but in many cases the only test of hearing has been the Preyer reflex, which cannot be taken to indicate normal thresholds for cochlear

FIGURE 8.2. Paint-filled inner ears showing two types of malformation. (A) and (C) are controls at the same age as the mutants (B) and (D), respectively. (B) This mutant, one day after birth, shows a truncation of the lateral canal, shown by the asterisk. (D) The mutant represented, embryonic day 14.5, shows complete lack of development of the semicircular canals. The vestibular part of the inner ear remains as a cyst-like structure, and the endolymphatic sac (es) is enlarged. ssc, superior semicircular canal; psc, posterior semicircular canal; lsc, lateral semicircular canal; ut, utricle; sac, saccule; cd, cochlear duct; es, endolymphatic sac; cc, crus commune.

activity (Kiernan et al. 1999). Furthermore, as for outer and middle ear defects, many of the knock-out mutants show early death, precluding assessment of cochlear function by most standard physiological approaches; cochlear function can be first detected at around twelve days after birth in normal mice.

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The inner ear develops from a thickening of the surface ectoderm at the side of the developing head, called the otic placode. This placode invaginates into a pit that closes off from the surface to form the otic vesicle or otocyst, lying just lateral to the neural tube. At first an ovoid shape, this otocyst begins to develop into the characteristic shape of the mature inner ear (Fig. 8.2). The endolymphatic duct is the first structure to protrude, from the dorsomedial region of the otocyst. Several mutants, such as kreisler and the Fgf3 and Hoxa1 knockout mutants, fail to form a normal endolymphatic duct, and subsequent development of the inner ear is severely abnormal. Much of the dorsal region of the otic vesicle forms the vestibular part of the ear, while the ventral tip extends and coils round to form the cochlea. Semicircular canals form from flattened semicircular pouches extending from the dorsal region of the otic vesicle. The central regions of these pouches meet in the middle and the cells there move away to leave an open rim around the edge, the semicircular canal (Martin and Swanson 1993). The lateral canal is the last to form, which might explain why it is the only canal to be affected, or is the most commonly affected canal, in some mouse mutants as well as in humans. The perilymphatic compartments form around the shape of the otic vesicle, by the resorption of mesenchymal cells to leave fluid-filled channels, and the bony labyrinth forms around this template by condensation of mesenchyme to form cartilage, followed by bone deposition.

What is it that controls the development of the complex form of the labyrinth? It has long been thought that surrounding tissues, particularly the neural tube, have a role in patterning the otic vesicle, helping to determine the fate of each part (Deol 1966a; Torres and Giraldez 1998). Recent observations that mutation of some genes that are not normally expressed in the otic vesicle can still lead to severe inner ear malformations provides striking evidence that this is indeed the case. An example of this is the Hoxa1 gene, which is expressed in the adjacent neural tube, but not in the otic vesicle: knockout of this gene leads to severe inner ear malformation, presumably by a failure of the neural tube in the mutant to provide the correct inductive signals to pattern the otic vesicle (Chisaka et al. 1992; Lufkin et al. 1991). Fekete (1996) has proposed a model to explain how the surrounding tissues might influence the creation of compartments within the otocyst. These compartments are marked by expression of various genes in restricted regions of the otic epithelium. Of course, mutations in the genes that are expressed in the otocyst can also lead to abnormal inner ear morphogenesis. Several genes that are implicated in morphogenetic defects of the inner ear are expressed in the otic epithelium in positions that correlate reasonably well with the defect seen. For example, Pax2 is expressed in the ventral otic vesicle, and mutation of the gene leads to absence of the cochlea (Favor et al. 1996; Torres et al. 1996), while Hmx3 is expressed in the dorsal otic vesicle, and knockout of this gene leads to gross malformation of the vestibule (Hadrys et al. 1998; Wang et al. 1998).

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semicircular canal. These defects can affect the determination of cell fate in the neuroepithelium, the differentiation of cell types, the sculpting of the tissues as they develop, or the function of the various cell types, including hair cells. Table 8.3 lists the mouse mutants with this type of abnormality.

TABLE 8.3. Mouse mutants with neuroepithelial defects