Учебники / Genetics and Auditory Disorders Keats 2002

showed variable severity and variable age of onset ranging from approximately 7 to 30 years of age. A genome-wide screen for linked polymorphic markers yielded a peak lod score of 3.87 for marker D11S4171, with the recombinants defining a 12-cM critical region that includes the DFNA12 locus on 11q22-q24 (Fig. 6.1). However, a peak multipoint lod score of 2.69 was also found for markers linked to DFNA2 at 1p32 in the same family (Balciuniene et al. 1998). Since a lod score of ≥3.0 is considered minimal statistical evidence of linkage, the observation of weak linkage to 1p32 is provocative, but not statistically significant. It is possible that the markers near DFNA2 are showing weak linkage by chance alone. Alternatively, these results may indicate that two different DFNA genes are segregating in this family, each of which independently causes hereditary hearing loss. It is also possible that there is an interaction or additive effect of mutations at DFNA2 and DFNA12 that cause the observed phenotypic heterogeneity in this family.

This latter hypothesis is consistent with the observation that, with a single exception, the most severely affected family members had haplotypes linked to both DFNA2 and DFNA12. However, individuals with milder hearing loss and later mean age of onset had haplotypes linked either to DFNA2 or DFNA12, but not to both (Balciuniene et al. 1998). Definitive proof of digenic inheritance of the hearing loss phenotype in this Swedish family will require identification of two non-allelic-dominant mutations in the most severely affected individuals: one in DFNA12 and one in DFNA2 or a closely linked locus.

3.20 Summary of the Molecular Genetics of DFN, DFNB and DFNA Loci

Generalizations about the nonsyndromic hearing loss loci have emerged from clinical characterization of families with NSRD, and from mapping and identifying these genes.

(1) The issue of genetic heterogeneity is usually circumvented in studies of hereditary hearing loss in consanguineous families and geographical and cultural isolates, since they are often segregating a single mutant allele for hearing loss. Affected individuals are likely to be homozygous for the same alleles of the disease gene and, just as importantly, the same alleles of closely linked markers (Friedman et al. 1995; Jaber et al. 1998; Sheffield et al. 1998). The size of the interval showing linkage dysequilibrium with the phenotype will vary inversely with the number of generations since the mutation was introduced.

(2) The mapping of over 30 DFNA and 30 DFNB loci provides abundant experimental data to support the claim that hearing loss is genetically heterogenous. Ongoing studies indicate that there are many more DFNA and DFNB loci to be mapped, since there are still additional families seg-

capsule. Approximately 8% of temporal bones from the Caucasian population show evidence of histologic otosclerosis, although only 1% of the Caucasian population manifests hearing loss associated with clinical otosclerosis (Altmann et al. 1967). The same study reported a lower prevalence of histologic otosclerosis in black, Asian, and American Indian populations (Altmann et al. 1967).

The hearing loss is typically conductive, but may progress to a profound mixed loss in later stages of the disease. The conductive component is caused by fixation of the stapes footplate in the oval window by otosclerotic tissue. The etiology of the sensorineural loss, termed “cochlear otosclerosis,” is not well understood, but has been postulated to be caused by direct mechanical effects, or by metabolic or vascular factors associated with the otosclerotic process within the cochlea. Fortunately, the conductive hearing loss may be reduced or eliminated by modern surgical techniques that re-establish efficient sound transduction from the ossicular chain to the vestibule (Shea 1998). Cochlear otosclerosis is not affected by these procedures, but its progression can be retarded by the oral administration of sodium fluoride (Causse et al. 1993).

Although 40 to 50% of cases appear to be sporadic, the hereditary nature of otosclerosis in other cases is well established and was recognized by Toynbee as early as 1861 (Toynbee 1861). A genetic etiology was also strongly suggested by the high concordance rate observed for monozygotic twins with otosclerosis (Fowler 1966). Most studies have concluded that inheritance of otosclerosis is autosomal dominant with reduced penetrance (Causse and Causse 1984; Gapany-Gapanaviscius 1975; Larsson 1960; Morrison 1967). However, digenic inheritance of autosomal recessive genes (Bauer and Stein 1925), as well as autosomal recessive and X-linked dominant genes (Hernandez-Orozco and Courtney 1964) have been proposed. These data, as well as other epidemiologic, clinical, and molecular studies indicate in toto that otosclerosis is not a simple monogenic Mendelian trait, but has a multifactorial, if not multigenic, etiology and pathogenesis.

Several different lines of evidence have implicated nongenetic factors. There is a slight preponderance of females among reported cases of otosclerosis and numerous reports of hearing loss exacerbation during pregnancy, suggesting an influence of sex hormones on progression, but not necessarily prevalence, of the otosclerotic process. Other studies have addressed the possibility of a viral etiology for otosclerosis. Mumps, rubella, and measles virus antigens have all been detected in otosclerotic foci, and recent studies utilizing RT-PCR have demonstrated measles virus RNA in otosclerotic temporal bones (McKenna et al. 1996; Niedermeyer and

Arnold 1995). Viral material was not detected in control temporal bone specimens in these analyses, supporting the hypothesis of a specific association of viral infection with otosclerosis, although the evidence does not establish a causal link. Finally, others have implicated immune mechanisms in otosclerosis, including autoimmunity to type II collagen (Yoo 1984). Oto-

164 A.J. Griffith and T.B. Friedman

sclerosis is likely to result from an interplay between at least some or all of these genetic, hormonal, infectious, and immunologic factors.

4.1 A Locus Associated with an Otosclerotic Phenotype

One important advance has been the mapping of a locus for otosclerotic hearing loss (OTS) to chromosome 15q25-q26 in a single family from India with no recorded consanguinity (Tomek et al. 1998) (Table 6.1). A somewhat higher degree of penetrance in this kindred facilitated the detection of linkage, as only three of 16 family members who inherited the OTSlinked haplotype did not have clinically detectable otosclerosis. The identification of a gene associated with otosclerotic hearing loss would provide an important molecular foundation for delineating this complex process, although mutations in OTS may not account for many, if not most, cases of otosclerosis.

4.2 Osteogenesis Imperfecta (OI) and Hearing Loss

Osteogenesis imperfecta (OI; chromosome 7) is a syndrome known to cause a stapes fixation phenotype similar to that of otosclerosis. OI is a dominant disorder caused by mutations in the a1 or a2 subunits of type I collagen, which result in abnormal bone remodeling and formation (Byers 1993). The OI phenotype is variably expressed and includes brittle or deformed bones, hyperextensible joints, and blue sclerae in addition to conductive hearing loss. An allele association study demonstrated linkage disequilibrium between otosclerosis and markers at the COL1A1 locus encoding the a1 subunit of type I collagen (McKenna et al. 1998). The authors hypothesized that otosclerosis may be associated with heterozygous null alleles of COL1A1 that are similar to those found in mild cases of OI.

These results suggest models for the etiology of otosclerosis. One model is that histologic otosclerosis is caused by a viral infection in individuals carrying heterozygous mutations in COL1A1, OTS, or other genes yet to be identified. Good candidates would be genes encoding extracellular matrix molecules, such as other collagens. The subsequent progression of otosclerosis might then be affected by hormonal factors such as those associated with pregnancy. The causal relationship between viral infection and otosclerosis may be direct or indirect, involving immune or autoimmune mechanisms that are triggered by the infection.

These first steps toward the identification of genetic loci associated with otosclerosis provide an important foundation for testing these models.

Future identification of molecular genotypes at COL1A1 and OTS will help clarify the roles of other causative factors. The elucidation of complex multigenic traits in other systems is just beginning to evolve, and otosclerosis should be an excellent auditory model system in which to apply those approaches.

5. Syndromic Hearing Impairment

Hearing loss may occur in association with pathologies affecting virtually any of the other organ systems, in which case it is called syndromic deafness. There are at least several hundred forms of syndromic hearing loss that are postulated to account for approximately one-third of the cases of genetic hearing loss (Gorlin et al. 1995) (Table 6.5). Deafness syndromes and their loci are often named after the clinician(s) who discovered the syndrome, such as the Waardenburg syndrome named after Petrus J. Waardenburg. Alternatively, the name of the syndrome may be based upon the phenotype, as in Branchial-Oto-Renal syndrome (BOR; Fig. 6.1 and Table 6.5). The name for a newly described deafness syndrome can be assigned by the HUGO Nomenclature Committee before the gene is mapped. This is because the new syndrome is, by definition, different from all other described deafness syndromes. Nevertheless, two clinically distinct syndromic forms of deafness may be due to allelic mutations in the same gene (i.e., allelic heterogeneity). Examples of clinically distinct syndromes caused by allelic mutations are the Marshall and Stickler syndromes, both of which can be caused by mutations in COL11A1 (see Section 5.1). Furthermore, Waardenburg syndrome type I (MIM 193500),Waardenburg syndrome type III (OMIM 148820) and Craniofacial-Deafness-Hand syndrome (OMIM 122880) are examples of allelic mutations of PAX3 (Asher et al. 1996).

Identification and analysis of syndromic hearing loss genes should provide insight into all types of hearing impairment, including nonsyndromic hearing loss. For example, there are alleles of genes causing syndromic hearing loss that are associated with nonsyndromic cases. Mutations of the MYO7A gene can cause nonsyndromic deafness DFNA11 and DFNB2, as well as hearing loss with retinitis pigmentosa in Usher syndrome type IB (Liu et al. 1997b; Liu et al. 1997c; Weil et al. 1995; Weil et al. 1997).

Similarly, mutations of PDS may cause nonsyndromic deafness DFNB4 or Pendred’s syndrome (see Section 5.2) (Everett et al. 1997; Li et al. 1998). There will likely be additional examples of allelism of syndromic with nonsyndromic hearing loss mutations as hearing loss genes continue to be identified.

Many types of syndromic hearing loss are likely to share similar pathogenetic mechanisms in the inner ear and other affected organ systems. Elucidation of the pathogenesis of auditory dysfunction may therefore be achieved by analogy to the etiopathogenesis of disease processes occurring in the other organ systems. This is especially useful given the paucity of auditory histopathologic data for the vast majority of genetic sensorineural hearing loss. For example, the well characterized basement membrane pathology observed in the progressive nephritis of Alport syndrome (sensorineural hearing loss in association with progressive nephritis) may share some pathogenetic features with the cochlea, and could facilitate our understanding of how auditory dysfunction occurs in these patients.