Учебники / Genetic Hearing Loss Willems 2004

children or young adults, the audiograms of Usher III persons look like those of type II but as they age, the hearing deteriorates into the severe-to- profound range typical of Usher type I; it is believed that Usher III individuals also develop vestibular areflexia over time. These distinctions between type I, II, and III are not perfect and there are a few cases that are intermediate (5,24,25). A subset of atypical type I cases have profound prelingual hearing loss and walk at a normal age showing a normal vestibular response (30). Some atypical type II individuals have been reported to have subnormal vestibular responses and others have demonstrated a progressive hearing loss (24,37,40).

At least 11 di erent genes have been identified, each responsible for a di erent subtype. For the most, mutations in each gene produce a fairly consistent phenotype, but there are interesting exceptions, discussed below. Usher type I has been found to be associated with four di erent mutations at genes MYO7A(11q), HARM(11p), CDH23(10q), and PCDH15(10q) (2,11,38,43). The USH2A and USH3 genes have also been identified (13,19). These six genes harbor mutations that cause each of the three clinical Usher types. About one-third of all Usher cases are due to genes that remain to be identified. The locations of four of these have been found: 3p (Usher IIb), 5q (Usher IIc), 14q (Usher Ia), 21q (Usher If), and 17q (Usher Ig) (12,16,20,29,32). Usher IId has been tentatively recognized by virtue of its lack of linkage to the regions know to contain the other Usher genes (32). The appears to be a certain degree of phenotypic specificity for the molecular subtypes (5,17), but there is also considerable overlap.

II.USHER TYPES

A.Usher Type Ib

Usher type Ib is due to mutations in the gene MYO7A on chromosome 11q (43). MYO7A encodes the protein myosin VIIa, a molecular motor that moves along actin filaments using energy obtained from the hydrolysis of ATP. The myosin VIIa molecular consists of three major sections, the head, neck, and tail. The head is the motor domain and possesses the actin binding site as well as a site to catalyze ATP hydrolysis. The head region is highly conserved across di erent myosins. The neck region is composed of five isoleucine-glutamine (IQ) motifs, which are predicted to bind calmodulin. The tail di ers from one type of myosin to another and is believed to confer binding specificity through its protein-protein interacting domains. Myosin VIIa has a motility that is calmodulin dependent and is mediated through an interaction with an actin filament (36).

small intracellular domain, a long extracellular domain, and, of course, a transmembrane domain. The extracellular domain is composed of 27 extracellular cadherin (EC) repeats, most of which possess Ca2C-binding motifs characteristic of cadherins. These motifs may be responsible for mediating cell-cell adhesion through a calcium-dependent interaction with other. The single transmembrane domain is followed by a short 268-amino- acid cytoplasmic region. This cytoplasmic domain contains two PDZbinding interfaces (PDI), which have been shown to interact with PDZ1 and PDZ2 domains of harmonin (33). There is alternative splicing, which allows for the inclusion of an additional 68 amino acids in the cochlear form vis-a-vis the retinal form. The added amino acids are believed to reduce the strength of the interaction of cadherin 23 internal PDI with PDZ1 of harmonin in the cochlea freeing the PDZ1 for other protein-protein interactions (33).

C.Usher Type If

Usher type If is due to mutation in the protocadherin 15 gene (2,4). These mutations produce a phenotype in both mouse and human that is similar to that produced by mutations in cadherin 23. The PCDH15 gene is located close to the CDH23 gene on chromosome 10q. Protocadherin 15 is a novel member of the cadherin superfamily. It has the same basic overall structure seen with cadherin 23, in that it possesses a large extracellular domain, a transmembrane domain, and a unique cytoplasmic domain with two highly conserved proline-rich regions. Proline-rich regions are known to serve as binding sites for several protein, among which are profilin, which regulates polymerization of actin filaments, and proteins containing SH3 and WW motifs, which participate in the assembly of signaling complexes (4). The pattern of expression in the inner ear indicates that protocadherin 15 protein lies in the stereocilia, suggesting. that it may participate in the cadherin 23/ harmonin complex (4).

Observation of stereociliary disruption of the Ames waltzer mouse suggests that protocadherin may play a role in the regulation of planar polarity, specifically in the orientation of the stereociliary bundle. Though also expressed in other areas of the cochlea, namely the supporting cells and outer sulcus cells as well as the spiral ganglion, the early morphological defect in the mouse appears to a ect only the stereocilia, with preservation of the inner and outer cell bodies. The function in the retina is not well understood. But, it is expressed in human adult and fetal inner outer synaptic layers, in the nerve fiber layer, and, in just the adult, in the outer limiting membrane of photoreceptor inner segments (3,4).

D.Usher Type Ic

French Acadians have been known to have a high frequency of Usher type I, thought to be due to a founder e ect (22). That type of Usher syndrome was found to genetically di erent from the Usher syndrome due to MYO7A mutations, and has been labeled Usher type Ic (35). A PDZcontaining protein coded for by a gene on chromosome 11p has been shown to be responsible for this type of Usher syndrome and the Acadian mutation has been identified as a 2916G > A a ecting splicing (9,38). While mutations in USH1C are frequent in the French Acadians, Usher type Ic is not limited to that population. One mutation, 238insC, was detected in several European individuals (38) who shared a common haplotype, suggesting a common origin for that allele (46). Several other mutations have also been observed. The USH1C gene codes for several alternatively spliced transcripts. In the mouse, these transcripts correspond to at least eight harmonin isoforms, ranging from 420 to 910 amino acids in length (38). The protein consists of two or three PDZ domains, one or two coiled-coil domains, a PST (proline-serine-threonine) domain, and a PBI domain at the carboxy terminus.

E.Usher Type IIa

Usher type IIa is the mildest of the Usher syndromes identified to date. The hearing loss ranges from mild to moderate in the low frequencies to severe to profound in the higher frequencies. About 10% of patients with Usher II experience a progressive hearing loss, but the progression is slower than that seen with Usher type III. The retinitis pigmentosa is reported to be milder. Usher type II is probably the most common form of Usher syndrome, being twice as frequent as Usher type I in some patient series.

The USH2A gene is located on chromosome 1q41 and has been identified as encoding a novel protein with partial homology to the laminin protein group (13). The gene has 21 exons and the protein has 1546 amino acids. The protein has a signal peptide at the amino end, a thrombospondin domain, a laminin N-terminal module (LN) followed by a series of laminin- EGF-like domains, and four fibonectin modules. The protein has been given the name usherin. Usherin is found in association with collagen in basement membranes of the inner ear and retina and is believed to act either as a structural component of the basement membrane or as part of a signaling system between that and cells it supports. Missense mutations in the LE domain have been found to disrupt the binding of usherin to type IV collagen, demonstrating one mechanism whereby USH2A mutations can cause the Usher II phenotype (8).

F.Usher Type III

Usher syndrome type III (USH3) is unique among the three clinical subtypes of Usher syndrome in that it shows postlingual, progressive hearing loss and late onset of retinitis pigmentosa, along with a progressive loss of vestibular function. A relatively small, compared to the other Usher genes, and novel gene was identified that was reported to have a limited homology to stargazen, a four-transmembrane-domain protein present in cerebellar synapses (1,18). Thus, it was postulated that clarin-1 may function at the level of hair cell and photoreceptor synapses. The gene is expressed in the retina, skeletal muscle, testis, and olfactory epithelium. Specific expression of clarin-1 was also observed in the inner and outer hair cells (1).

Usher type II is common in the Finnish population. One mutation, Y100X, was found to account for most of the Finnish cases (19). 144T>G mutation was found to be responsible for the majority of cases of Usher III seen in individuals of Askenazi descent (1,14). Overall, USH3 mutations appear to be responsible for no more than 3% of all Usher cases.

G.Other Usher Types

Fives types of Usher syndrome are still unidentified. Usher type I loci are know to exist on chromosomes 14q, 21q, and 17q (12,20,29). Two additional Usher II loci are located on chromosome 3p and 5q (16,32).

III.CONCLUSIONS

Usher syndrome is the most common form of combined hearing and visual impairment in Europe and the United States. As such, it causes a considerable burden to society as well as to the individuals and families involved. Research into the causes of this disorder is progressing at a rapid pace with identification of six of the 11 genes know to be involved. The identification of the leads has led directly toward a better understanding of the underlying mechanisms by which changes in these proteins cause this combined sensory defect. Four of the proteins, usherin, harmonin, protocadherin 15, and clarin 1, are novel and the discovery of their very existence was predicated on research into this rare disorder. The two other proteins, myosin VIIA and cadherin 23, were know but their function in the ear and eye was not realized until the discovery of the link between those genes and Usher syndrome. Unraveling the roles of genes that impact on the two most important human senses not only serves to push us further toward the development of e ective

therapies but also provides new insights into the basic cell biology of vision and hearing.

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