Review
Molecular basis of human Usher syndrome: Deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease

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Abstract

Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. It is clinically and genetically heterogeneous and at least 12 chromosomal loci are assigned to three clinical USH types, namely USH1A-G, USH2A-C, USH3A (Davenport, S.L.H., Omenn, G.S., 1977. The heterogeneity of Usher syndrome. Vth Int. Conf. Birth Defects, Montreal; Petit, C., 2001. Usher syndrome: from genetics to pathogenesis. Annu. Rev. Genomics Hum. Genet. 2, 271–297). Mutations in USH type 1 genes cause the most severe form of USH. In USH1 patients, congenital deafness is combined with a pre-pubertal onset of retinitis pigmentosa (RP) and severe vestibular dysfunctions. Those with USH2 have moderate to severe congenital hearing loss, non-vestibular dysfunction and a later onset of RP. USH3 is characterized by variable RP and vestibular dysfunction combined with progressive hearing loss. The gene products of eight identified USH genes belong to different protein classes and families. There are five known USH1 molecules: the molecular motor myosin VIIa (USH1B); the two cell–cell adhesion cadherin proteins, cadherin 23 (USH1D) and protocadherin 15, (USH1F) and the scaffold proteins, harmonin (USH1C) and SANS (USH1G). In addition, two USH2 genes and one USH3A gene have been identified. The two USH2 genes code for the transmembrane protein USH2A, also termed USH2A (“usherin”) and the G-protein-coupled 7-transmembrane receptor VLGR1b (USH2C), respectively, whereas the USH3A gene encodes clarin-1, a member of the clarin family which exhibits 4-transmembrane domains. Molecular analysis of USH1 protein function revealed that all five USH1 proteins are integrated into a protein network via binding to PDZ domains in the USH1C protein harmonin. Furthermore, this scaffold function of harmonin is supported by the USH1G protein SANS. Recently, we have shown that the USH2 proteins USH2A and VLGR1b as well as the candidate for USH2B, the sodium bicarbonate co-transporter NBC3, are also integrated into this USH protein network. In the inner ear, these interactions are essential for the differentiation of hair cell stereocilia but may also participate in the mechano-electrical signal transduction and the synaptic function of maturated hair cells. In the retina, the co-expression of all USH1 and USH2 proteins at the synapse of photoreceptor cells indicates that they are organized in an USH protein network there. The identification of the USH protein network indicates a common pathophysiological pathway in USH. Dysfunction or absence of any of the molecules in the mutual “interactome” related to the USH disease may lead to disruption of the network causing senso-neuronal degeneration in the inner ear and the retina, the clinical symptoms of USH.

Introduction

Human communication and perception of the environment are mainly formulated on information imported through the ear and the eye. Chronic diseases affecting the inner ear and the retina cause severe impairments of our communication systems. There are about 40 known human syndromes which include the symptoms of blindness in combination with deafness. In more than half of the cases, the Usher syndrome is the origin of this defect (Gorlin, 1995, Vernon, 1969). The human Usher syndrome (USH) is defined by congenital, bilateral deafness and a later onset of the loss of the visual field, caused by retinitis pigmentosa (RP). In RP, retinal degeneration is based on photoreceptor cell death which occurs from the periphery to the macula of the retina. Night blindness is the first symptom of RP, followed by narrowing of the visual field (“tunnel vision”) and later to complete blindness (van Soest et al., 1999, Wang et al., 2005). These visual deficits are triggered by any one of over 130 mutated genes (Tschernutter et al., 2005). USH is the most common cause of combined deaf-blindness (Vernon, 1969) and the most frequent form of recessive RP (Keats and Corey, 1999).

One of the earliest descriptions of USH was given by Albrecht von Graefe, a pioneer of modern ophthalmology. He reported a case of a deaf and dumb male patient with retinal degeneration who had two equally affected brothers (von Graefe, 1858). Subsequently his student Richard Liebreich, screened the population of Berlin for syndromes including RP and reported similar observations (Liebreich, 1861). He emphasized the recessive nature of the disease by commenting on the combination of congenital deafness with RP in several siblings from either consanguineous marriages or families with several members affected in different generations. The disease was eventually named after Charles Usher, a Scottish ophthalmologist who described the hereditary nature of this disorder in 19 cases out of 69 RP patients (Usher, 1914).

Based on the heterogenic clinical course of the disease described by Bell (1922) and Hallgren (1959) and co-workers, USH was subdivided into three clinical types, namely USH1, USH2 and USH3 (Davenport and Omenn, 1977). USH type 1 is the most severe form of this disease. USH1 patients are deaf at birth and the onset of RP is pre-pubertal. Most, but not all USH1 patients exhibit severe dysfunction of the vestibular system which leads to a further subdivision of USH type 1 (Otterstedde et al., 2001). USH type 2 is characterized by a constant moderate to severe hearing impairment from birth on and RP can be diagnosed during puberty (Reisser et al., 2002). USH type 3 (USH3) is distinguished from USH1 and USH2 by the later initiation of deafness combined with variable RP and vestibular dysfunction. In USH3 patients, the hearing impairment is progressive starting post-lingual and RP is diagnosed in most cases between the 2nd and 4th decade of life (Pakarinen et al., 1995, Petit, 2001). The classification into three USH types is still being used, although the increasing scientific knowledge through the end of the last century has revealed an even larger genetic heterogeneity to USH. To date, 12 independent loci on different chromosomes have been identified whose inherited defects lead to the development of USH. The loci defect dictates the subdivision into further subtypes, USH1A-G, USH2A-C, and USH3A as summarized in Table 1. Currently, an affected gene has been determined for eight different USH loci (Ahmed et al., 2003, Petit, 2001, Weil et al., 2003, Weston et al., 2004). However, in at least four of these genes, some mutations cause USH while others result in non-syndromic hearing loss. These USH genes are MYO7A for USH1B and DFNB2/DFNA11 (Liu et al., 1997b, Liu et al., 1997c) and CDH23 for USH1D and DFNB12 (Astuto et al., 2002, Bork et al., 2001), PCDH15 for USH1F and DFNB23 (Ahmed et al., 2003) and USH1C for USH1C and DFNB18 (Ahmed et al., 2002, Ouyang et al., 2002). Some mutations in the USH2A gene cause isolated RP (Rivolta et al., 2000).

Epidemiological studies of USH show a prevalence of 3–6 patients per 100,000 inhabitants of the developed world (Boughman and Fishman, 1983, Forsius et al., 1971, Grondahl, 1987, Hope et al., 1997, Rosenberg et al., 1997, Spandau and Rohrschneider, 2002). Since false diagnosis of RP occurs frequently in infants, the prevalence is more likely to be 1/10,000 (Hope et al., 1997). The numbers of patients affected by the three distinct USH types is unequal. Studies in Europe show a proportion of 25–44% of USH1 patients and 56–75% of USH2 patients (Grondahl, 1987, Hope et al., 1997, Rosenberg et al., 1997, Spandau and Rohrschneider, 2002). Regional founder effects contribute to the described wide bandwidth of subtype prevalence. For example, USH3 in total accounts for a very low percentage (∼ 2%), but in contrast contributes in Birmingham (UK) for 20% of all USH cases and even higher percentage, 42%, in Finland (Hope et al., 1997, Pakarinen et al., 1995).

In addition to the characteristic senso-neuronal degeneration in the eye and the inner ear of USH, several reports indicate that USH affects other tissues and organs. This is confirmed by the rather wide expression profiles of all USH gene products obtained (see below). Functional studies on USH1 and USH2 patients indicate lower odor identification ability (Zrada et al., 1996). However, a study by Seeliger et al. (1999) on olfaction in USH did not confirm differences between USH patients and the control group. Nevertheless, recent expression analyses revealed that all analyzed USH molecules are expressed in the olfactory epithelium (Mikosz, 2005, Wolfrum et al., 1998 and Mikoz and Wolfrum, unpublished). Thus, the analysis of biopsies from the nasal epithelium of patients may be useful for USH diagnosis (Cohn et al., 2004). Furthermore, USH may also be related to brain dysfunction. An increase of mental deficiencies, cerebral atrophies, and ataxies are reported for USH patients (Drouet et al., 2003; Hess-Röver et al., 1999, Koizumi et al., 1988, Mangotich and Misiaszek, 1983). Despite the expression of all known USH proteins in the brain (Wolfrum et al., unpublished), often USH patients are highly educated and intelligent.

Sparse histopathological data from patients are often related to undefined USH subtypes. In some cases, ciliary abnormalities have been reported in patients of undefined USH subtype in retinal photoreceptors (connecting cilium) and the nasal epithelium, the trachea, and sperm cells (e.g. Arden and Fox, 1979, Baris et al., 1994, Barrong et al., 1992, Hunter et al., 1986, Tosi et al., 2003, Petrozza et al., 1991, van Aarem et al., 1999). Based on these observations, it has been suggested that USH is related to cilia dysfunction. When myosin VIIa, the product of the first identified USH gene, was localized in the connecting cilium of photoreceptor cells (Liu et al., 1997a), the latter suggestion warrants further attention.

The presence of cilia is one of the structural similarities between retinal photoreceptor cells and the mechanosensitive hair cells of the inner ear (Fig. 1). In photoreceptor cells, the connecting cilium, which is homologous to the transition zone found at the base of every motile cilium, links the biosynthetic and metabolic active inner segment with the outer segment, which is actually a modified cilium (Besharse and Horst, 1990). Each hair cell possesses one kinocilium which is responsible for organizing the array of stereocilia during hair cell differentiation (Kelley et al., 1992, Sobkowicz et al., 1995). In the mammalian cochlea, this “real” cilium disappears during hair cell maturation. The stereocilia, structures that take up the mechanical stimulus in hair cells, are not “real” cilia. On contrary, they are highly specialized microvilli (“stereovilli”) characterized by a rigid actin filament core (Tilney et al., 1988). Microvillar-like, actin filament-supported structures are also found in photoreceptor cells in the form of calycal processes at the apical membrane of the inner segment (Nagle et al., 1986). These calyces sheath the base of the photoreceptor outer segment and thereby may stabilize it. Microvillar-like differentiations are more obvious on the apical membrane of the cells of the retinal pigment epithelium. Furthermore, ribbon synapses are characteristic for both types of sensory cells. Their synapses are a unique type of chemical synapses structurally and functionally specialized for massive and sustained neurotransmitter release (Rao-Mirotznik et al., 1995, Wagner, 1997). Thus, the primary targets for defects caused by USH are probably molecules which are present in the subcellular compartments with the described similarities between both types of sensory cells. The molecular dissection of these subcellular compartments could reveal candidate genes for USH, while the study of the identified molecules related to USH should provide insights into novel processes shared by both types of sensory cells.

Section snippets

Characteristics and function of the proteins encoded by the identified USH genes

Of the three clinically characterized types of USH, eight genes on 12 USH loci have been cloned. The protein products of the eight USH genes, belong to different protein classes and therefore possess various cellular functions (Table 1).

Animal models for USH

Mouse models that mimic the mutant phenotypes of human diseases are important in the development of therapies. At least one mouse model exists or is currently under generation for all USH types (Table 1).

Mouse mutants defective for USH1 proteins myosin VIIa (Shaker-1) (Gibson et al., 1995, Mburu et al., 1997), cadherin 23 (Waltzer) (Di Palma et al., 2001a), protocadherin 15 (Ames waltzer) (Alagramam et al., 2001a), harmonin (Deaf circler), harmonin isoform b (Deaf circler-2J) (Johnson et al.,

USH protein network is co-ordinated by the key organizer harmonin, an interactome related to USH

From growing evidence emerges the picture that all proteins related to the currently identified USH genes are organized in a protein network. Several studies describe protein–protein interactions between USH1 protein suggesting an USH1 protein network (Boëda et al., 2002, Siemens et al., 2002, Adato et al., 2005, Reiners et al., 2005a). More recently, we have shown that USH2 proteins are also integrated within this USH1/2 protein network (Reiners et al., 2005b, Reiners and Wolfrum, 2006).

Perspectives in therapy of USH

USH patients suffer from congenital hearing loss and RP starting in childhood or even later in the 2nd to 4th decade of life. Gene therapy shows great promise for the treatment of monogenic diseases. In most forms of USH, with exception of USH3, the hearing impairment of USH patients originates in developmental failures of the inner ear hair cells (see above). Therefore prenatal inner ear treatments are necessary. However, gene therapy strategies based on prenatal treatment are currently not

Acknowledgements

Our work is supported by DFG GRK 1044, Forschung contra Blindheit - Initative Usher Syndrom e.V., ProRetina Deutschland e.V., and the FAUN-Stiftung, Nürnberg, Germany. The authors thank Brenda K. Huntley for her helpful comments on the manuscript and attentive linguistic corrections. K.N.W. and U.W. also thank Lisa for her patience.

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    1

    Both authors contributed equally to this work.

    2

    Present address: Abbott GmbH, Knollstr., 67061 Ludwigshafen, Germany.

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