Molecular Genetics of Usher Syndrome

Hannie Kremer, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Erwin van Wijk, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Published online: March 2009

DOI: 10.1002/9780470015902.a0021456

Usher syndrome affects hearing, vision and balance. The syndrome is genetically heterogeneous and nine causative genes have been identified so far. Proteins encoded by these genes function in a protein network at different subcellular locations in photoreceptor cells of the retina and hair cells of the inner ear. In hair cells, Usher proteins mainly contribute to the formation of fibrous links that connect stereocilia and also the stereocilia and the kinocilium. In addition, Usher proteins are found in the synaptic region where hair cells contact nerve fibres. In photoreceptor cells the Usher proteins are mainly seen in the region of the connecting cilium including the periciliary region of the cell body, the connecting cilium itself and the basal body and accessory centriole. In addition, Usher proteins are present in the synaptic region of photoreceptor cells. The Usher proteins are thought to have diverse functions including structural support, transport and signalling.

Key Concepts

Genetic Heterogeneity of Disorders

Genes involved in genetically heterogeneous disorders encode proteins that are functionally related. In the case of Usher syndrome, the genes involved encode proteins that function in a protein complex. Defects in different members of the complex lead to the same phenotype. See also Oti and Brunner (2007).

Keywords: inner ear; retina; hair cells; photoreceptor cells; Usher syndrome

Figure 1. Schematic representation of the architecture of the USH1 and USH2 proteins and their different isoforms. (a) The Usher 1B protein, myosin VIIa, is composed of a motor head domain, five calmodulin-binding IQ motifs, two FERM domains, two MyTH4 domains and a Src homology 3 (SH3) domain. (b) Three different classes of isoforms of the USH1C protein, harmonin, are identified. All three isoforms consist of two PDZ (PSD95, discs large, ZO-1) domains (PDZ1 and 2) and one coiled-coil domain. Class A isoforms contain an additional PDZ domain (PDZ3). The class B isoforms contain also this third PDZ domain, a second coiled-coil domain and a proline, serine, threonine-rich region (PST). Isoform A1 and B4 contain a C-terminal class I PDZ binding motif (PBM). (c) Representation of the three different isoforms of cadherin 23 (USH1D). Isoform A is composed of 27 Ca2+-binding extracellular cadherin domains (EC1-27), a transmembrane domain (TM) and a short intracellular region with a C-terminal class I PBM. Isoform B is similar to isoform A, but lacks the first 21 EC domains. Isoform C only consists of the intracellular region and C-terminal PBM. (d) Like cadherin 23, the nonclassical cadherin protocadherin 15 (USH1F) consists of either 11 (isoform A) or 1 (isoform B) EC domains, a transmembrane domain and a C-terminal class I PBM. (e) The scaffold protein SANS (USH1G) consists of three ankyrin domains (ANK), a central region (CENT), a sterile alpha motif (SAM) and a C-terminal class I PBM. (f) Isoform A of the Usher 2A protein (USH2A) contains an N-terminal thrombospondin/pentaxin/laminin G-like domain, a laminin N-terminal (LamNT) domain, ten laminin-type EGF-like (EGF Lam) and four fibronectin type III (FN3) domains. In addition to the domain structure of isoform A, isoform B contains two laminin G (LamG), 28 FN3, a transmembrane domain and an intracellular region with a C-terminal class I PBM. (g) Three isoforms of the G-protein coupled Receptor 98 kDa, GPR98 (USH2C), are identified. The longest isoform, isoform B, consists of a thrombospondin/pentaxin/laminin G-like domain, 35 Ca2+-binding calcium exchanger (Calx) domains, seven EAR/EPTP repeats, a seven-transmembrane region and an intracellular region containing a C-terminal class I PBM. Isoform A is composed of the last six C-terminal Calx domains, the seven-transmembrane region and the intracellular region with the C-terminal class I PBM. The predicted extracellular isoform C only contains the first 16 N-terminal Calx domains and the thrombospondin/pentaxin/laminin G-like domain. (h) Isoform A of whirlin, the USH2D protein, contains three PDZ domains and a proline-rich region (P). Isoform B lacks the two N-terminal PDZ domains. Both isoforms contain a C-terminal class II PBM. This figure was adapted from Kremer et al. (2006).
Figure 2. The Usher protein network. All identified protein–protein interactions are indicated (references: see text). Red indicates association with Usher syndrome type I (USH1), green indicates association with Usher syndrome type II (USH2), blue colour indicates association with isolated retinitis pigmentosa (RP) and black indicates association with isolated deafness. The binding of cadherin 23 and protocadherin 15 to whirlin has been identified in a yeast two-hybrid assay (van Wijk et al., unpublished data). This figure was adapted from Kremer et al. (2006).
Figure 3. Schematic representation of the sensory cells in the inner ear and retina. (a) The apical side of the inner ear hair cell carries the highly organized, actin-filled stereocilia, in which the mechanotransduction takes place. The stereocilia are connected by the tip links, horizontal links, transient links and ankle links. The types of links change during development. The stereocilia are anchored in the actin-rich cuticular plate. The only true cilium, the kinocilium, is located lateral to the largest stereocilium and extends from the basal body. The synaptic junctions between hair cells (mainly in inner hair cells) and afferent neurons at the basal side of the hair cell, contain the ribbons. (b) The rod and cone photoreceptors, which are the main morphological subtypes of photoreceptor cells, are highly polarized. The photoreceptor outer segment, a highly modified cilium containing the phototransduction proteins, is separated from the inner segment by the connecting cilium. The periciliary region is situated next to the connecting cilium and the proximal outer segment. The nuclei of the photoreceptor cells are situated in the outer nuclear layer. The synaptic terminals, containing the ribbons, connect the photoreceptors with horizontal cells, bipolar cells and ganglion cells. This figure was adapted from Kremer et al. (2006).
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 References
    Abd-El-Barr MM, Sykoudis K, Andrabi S et al. (2007) Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet–Biedl syndrome. Vision Research 47: 3394–3407.
    Adato A, Lefevre G, Delprat B et al. (2005a) Usherin, the defective protein in Usher syndrome type IIA, is likely to be a component of interstereocilia ankle links in the inner ear sensory cells. Human Molecular Genetics 14: 3921–3932.
    Adato A, Michel V, Kikkawa Y et al. (2005b) Interactions in the network of Usher syndrome type 1 proteins. Human Molecular Genetics 14: 347–356.
    other Ahmed Z, Riazuddin S, Khan S et al. (2008) USH1 H, a novel locus for type I Usher syndrome, maps to chromosome 15q22-23. Clinical Genetics DOI:10.1111/j.1399-0004.2008.01038.x.
    Ahmed ZM, Goodyear R, Riazuddin S et al. (2006) The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15. Journal of Neuroscience 26: 7022–7034.
    Alagramam KN, Yuan H, Kuehn MH et al. (2001) Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Human Molecular Genetics 10: 1709–1718.
    book Bell J (1922) "Retinitis pigmentosa and allied diseases". In: Pearson K (ed.) The Treasury of Human Inheritance, vol. 2, pp. 1–29. London: Cambridge Press.
    book Besharse JC and Horst CJ (1990) "The photoreceptor connecting cilium – a model for the transition zone". In: Bloodgood RA (ed.) Ciliary and Flagellar Membranes, pp. 389–417. New York: Plenum.
    Boëda B, El Amraoui A, Bahloul A et al. (2002) Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO Journal 21: 6689–6699.
    Bok D, Galbraith G, Lopez I et al. (2003) Blindness and auditory impairment caused by loss of the sodium bicarbonate cotransporter NBC3. Nature Genetics 34: 313–319.
    Bolz H, von Brederlow B, Ramirez A et al. (2001) Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nature Genetics 27: 108–112.
    Brown SD, Hardisty-Hughes RE and Mburu P (2008) Quiet as a mouse: dissecting the molecular and genetic basis of hearing. Nature Reviews Genetics 9: 277–290.
    Cohen M, Bitner-Glindzicz M and Luxon L (2007) The changing face of Usher syndrome: clinical implications. International Journal of Audiology 46: 82–93.
    Cremers FP, Kimberling WJ, Kulm M et al. (2007) Development of a genotyping microarray for Usher syndrome. Journal of Medical Genetics 44: 153–160.
    Di Palma F, Holme RH, Bryda EC et al. (2001) Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nature Genetics 27: 103–107.
    Ebermann I, Scholl HP, Charbel IP et al. (2007) A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. Human Genetics 121: 203–211.
    El Amraoui A and Petit C (2005) Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells. Journal of Cell Science 118: 4593–4603.
    Gibbs D, Azarian SM, Lillo C et al. (2004) Role of myosin VIIa and Rab27a in the motility and localization of RPE melanosomes. Journal of Cell Science 117: 6473–6483.
    Goodyear R and Richardson G (1999) The ankle-link antigen: an epitope sensitive to calcium chelation associated with the hair-cell surface and the calycal processes of photoreceptors. Journal of Neuroscience 19: 3761–3772.
    Gosens I, van Wijk E, Kersten FFJ et al. (2007) MPP1 links the Usher protein network and the Crumbs protein complex in the retina. Human Molecular Genetics 16: 1993–2003.
    von Graefe A (1858) Exceptionelles Verhalten des Gesichtsfeldes bei Pigmententartung der Netzhaut. Archiv für Ophthalmologie 4: 250–253.
    Insinna C and Besharse JC (2008) Intraflagellar transport and the sensory outer segment of vertebrate photoreceptors. Developmental Dynamics 237: 1982–1992.
    Jacobson SG, Cideciyan AV, Aleman TS et al. (2008) Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. Human Molecular Genetics 17: 2405–2415.
    Johnson KR, Gagnon LH, Webb LS et al. (2003) Mouse models of USH1C and DFNB18: phenotypic and molecular analyses of two new spontaneous mutations of the Ush1c gene. Human Molecular Genetics 12: 3075–3086.
    Kachar B, Battaglia A and Fex J (1997) Compartmentalized vesicular traffic around the hair cell cuticular plate. Hearing Research 107: 102–112.
    Kalay E, de Brouwer AP, Caylan R et al. (2005) A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome. Journal of Molecular Medicine 83: 1025–1032.
    Kazmierczak P, Sakaguchi H, Tokita J et al. (2007) Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449: 87–91.
    Kremer H, van Wijk E, Märker T et al. (2006) Usher syndrome: molecular links of pathogenesis, proteins and pathways. Human Molecular Genetics 15(Spec No 2): R262–R270.
    Lagziel A, Ahmed ZM, Schultz JM et al. (2005) Spatiotemporal pattern and isoforms of cadherin 23 in wild type and waltzer mice during inner ear hair cell development. Developmental Biology 280: 295–306.
    Lefèvre G, Michel V, Weil D et al. (2008) A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth. Development 135: 1427–1437.
    Liu X, Bulgakov OV, Darrow KN et al. (2007) Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells. Proceedings of the National Academy of Sciences of the USA 104: 4413–4418.
    Märker T, van Wijk E, Overlack N et al. (2008) A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Human Molecular Genetics 17: 71–86.
    Mburu P, Mustapha M, Varela A et al. (2003) Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nature Genetics 34: 421–428.
    McGee J, Goodyear RJ, McMillan DR et al. (2006) The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles. Journal of Neuroscience 26: 6543–6553.
    Michalski N, Michel V, Bahloul A et al. (2007) Molecular characterization of the ankle-link complex in cochlear hair cells and its role in the hair bundle functioning. Journal of Neuroscience 27: 6478–6488.
    Michel V, Goodyear RJ, Weil D et al. (2005) Cadherin 23 is a component of the transient lateral links in the developing hair bundles of cochlear sensory cells. Developmental Biology 280: 281–294.
    Oti M and Brunner HG (2007) The modular nature of genetic diseases. Clinical Genetics 71: 1–11.
    Otterstedde CR, Spandau U, Blankenagel A et al. (2001) A new clinical classification for Usher's syndrome based on a new subtype of Usher's syndrome type I. Laryngoscope 111: 84–86.
    Reiners J, Nagel-Wolfrum K, Jurgens K et al. (2006) Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Experimental Eye Research 83: 97–119.
    Reiners J, van Wijk E, Märker T et al. (2005) Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2. Human Molecular Genetics 14: 3933–3943.
    Richard M, Roepman R, Aartsen WM et al. (2006) Towards understanding CRUMBS function in retinal dystrophies. Human Molecular Genetics 15(Spec No 2): R235–R243.
    Roepman R and Wolfrum U (2007) Protein networks and complexes in photoreceptor cilia. Subcellular Biochemistry 43: 209–235.
    Self T, Mahony M, Fleming J et al. (1998) Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells. Development 125: 557–566.
    Siemens J, Lillo C, Dumont RA et al. (2004) Cadherin 23 is a component of the tip link in hair-cell stereocilia. Nature 428: 950–955.
    Smith RJ, Berlin CI, Hejtmancik JF et al. (1994) Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium. American Journal of Medical Genetics 50: 32–38.
    Sterling P and Matthews G (2005) Structure and function of ribbon synapses. Trends in Neurosciences 28: 20–29.
    Tobin JL and Beales PL (2007) Bardet–Biedl syndrome: beyond the cilium. Pediatric Nephrology 22: 926–936.
    Van Wijk E, Kersten FFJ, Kartono A et al. (2008) Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein. Human Molecular Genetics DOI: 10.1093/hmg/ddn312
    van Wijk E, van der Zwaag B, Peters T et al. (2006) The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Human Molecular Genetics 15: 751–765.
    Zheng QY, Yan D, Ouyang XM et al. (2005) Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Human Molecular Genetics 14: 103–111.
 Further Reading
    book Dallos P, Popper AN and Fay RR (1996) The Cochlea. New York, NY: Springer.
    book Forrester JV, Dick AD, McMenamin PG and Roberts F (2008) The Eye. Basic Sciences in Practice. Edinburgh: Saunders-Elsevier.
    Goodyear RJ, Marcotti W, Kros CJ and Richardson GP (2005) Development and properties of stereociliary link types in hair cells of the mouse cochlea. Journal of Comparative Neurology 485: 75–85.

Related Sub-Topics:

Neurobiology of Disease | Sensory Systems | Sensory Transduction Mechanisms | Cellular Transport | Intracellular and Extracellular Signalling | Cell Cytoskeleton | Cell Motility | Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders
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Article Title: Molecular Genetics of Usher Syndrome
 
How to Cite close
Kremer, Hannie, and van Wijk, Erwin(Mar 2009) Molecular Genetics of Usher Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021456]