Molecular Genetics of Usher Syndrome: Current State of Understanding


Usher syndrome affects hearing, vision and balance. The syndrome is genetically heterogeneous and mutations in ten genes have been identified to be disease causing. Proteins encoded by these genes cofunction with each other and with other proteins, composing an Usher interactome with diverse functions including structural support, transport and potentially signalling at different subcellular locations in hair cells of the inner ear and in photoreceptors of the retina. In hair cells, Usher proteins mainly contribute to the formation of fibrous links, including the tip link, that connect stereocilia and stereocilia to the kinocilium. In addition, Usher proteins are found in the synaptic region where they might contribute to signal transduction by regulating the cell surface levels of Cav1.3 Ca2+ channels and exocytosis. In photoreceptor cells, the Usher proteins are seen in the region of the connecting cilium including the periciliary region, the basal body, accessory centriole and calyceal processes. Also here, Usher proteins are present in the synaptic region. Although the function of Usher proteins in photoreceptors and hair cells is not yet fully understood, promising therapeutic developments are ongoing to alleviate the phenotypic burden resulting from mutations in any of the Usher genes.

Key Concepts

  • Usher syndrome is clinically and genetically heterogeneous.
  • Usher syndrome type I (USH1) and type II (USH2) proteins interact and form highly dynamic protein networks.
  • Usher protein networks fulfil a role in providing structural support, play a role in intracellular transport mechanisms and are suggested to be involved in cellular signalling cascades.
  • A range of cellular and animal models are used to unravel the molecular pathogenesis of Usher syndrome and to evaluate promising therapeutic strategies.
  • Promising progress in the development of (pre)clinical genetic (i.e. gene augmentation, splice modulation, translational read‐through and gene editing) and nongenetic (i.e. small compounds, neurotrophic factors and cell replacement) therapeutic strategies have been published for Usher syndrome.

Keywords: Usher syndrome; Usher interactome; molecular pathogenesis; retinitis pigmentosa; hearing impairment; animal and cellular models; genetic therapy

Figure 1. Schematic representation of the architecture of Usher proteins and their different isoforms. (a) The USH1b protein, MYO7A, 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 the 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 also contain this third PDZ domain, a second coiled‐coil domain and a proline, serine, threonine‐rich region (PST). Isoform A1 and B4 contain a ‐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 SAM and a C‐terminal class I PBM. (f) Three isoforms are known for CIB2, the USH1j protein. All the three isoforms contain two EF‐hand domains (EFh). Variation in protein length is determined by alternative splicing in the 5′ and 3′ end of CIB2 transcripts, resulting in isoforms A, B and C. (g) Isoform A of the USH2a protein contains an N‐terminal thrombospondin/pentaxin/laminin G‐like domain, a laminin N‐terminal (LamNT) domain, ten laminin‐type EGF‐like (EGF Lam) domain 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. (h) Three isoforms of the adhesion G protein‐coupled receptor V1 (ADGRV1, USH2c) are identified. The longest isoform, isoform B, consists of a thrombospondin/pentaxin/laminin G‐like domain (depicted in green), 35 Ca2+‐binding calcium exchanger b (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. (i) Isoform A of whirlin, the USH2d protein, contains three PDZ domains and a proline‐rich region (indicated by 'P'). Isoform B lacks the two N‐terminal PDZ domains. Both isoforms contain a C‐terminal class II PBM. (j) The protein product of USH3a, clarin‐1, is present in three isoforms. Isoform A is the longest and consists of four transmembrane domains. Isoform C consists of two of these transmembrane domains, whereas isoform B consists of none of the transmembrane domains. (k) The USH2 modifier PDZD7 is structurally related to harmonin and whirlin and consists of three PDZ domains (isoform A). The smaller isoform B lacks the third PDZ domain. Adapted from Kremer et al. 2006 © Oxford University Press.
Figure 2. Schematic representation of the Usher protein network. All identified protein–protein interactions are indicated (references: see text). Boxes in red indicate an association with Usher syndrome type I (USH1), green indicates association with Usher syndrome type II (USH2), blue indicates association with isolated retinitis pigmentosa (RP), black indicates association with isolated deafness and orange indicates association as an Usher syndrome modifier. Adapted from Kremer et al. 2006 © Oxford University Press.
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 organised, 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 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 synaptic ribbons. (b) The rod and cone photoreceptors, which are the main morphological types of photoreceptors, are highly polarised. 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 photoreceptors are situated in the outer nuclear layer. The synaptic terminals, containing the ribbons, connect the photoreceptors with horizontal cells, bipolar cells and ganglion cells. Reproduced with permission from Kremer et al. 2006 © Oxford University Press.


Alagramam KN, Gopal SR, Geng R, et al. (2016) A small molecule mitigates hearing loss in a mouse model of Usher syndrome III. Nature Chemical Biology 12 (6): 444–451. DOI: 10.1038/nchembio.2069.

Bahloul A, Michel V, Hardelin JP, et al. (2010) Cadherin‐23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids. Human Molecular Genetics 19 (18): 3557–3565. DOI: 10.1093/hmg/ddq271.

Blanco‐Sanchez B, Clement A, Fierro J Jr, Washbourne P and Westerfield M (2014) Complexes of Usher proteins preassemble at the endoplasmic reticulum and are required for trafficking and ER homeostasis. Disease Models & Mechanisms 7 (5): 547–559. DOI: 10.1242/dmm.014068.

Blanco‐Sanchez B, Clement A, Phillips JB and Westerfield M (2017) Zebrafish models of human eye and inner ear diseases. Methods in Cell Biology 138: 415–467. DOI: 10.1016/bs.mcb.2016.10.006.

Caberlotto E, Michel V, Foucher I, et al. (2011) Usher type 1G protein sans is a critical component of the tip‐link complex, a structure controlling actin polymerization in stereocilia. Proceedings of the National Academy of Sciences of the United States of America 108 (14): 5825–5830. DOI: 10.1073/pnas.1017114108.

Cosgrove D and Zallocchi M (2014) Usher protein functions in hair cells and photoreceptors. International Journal of Biochemistry and Cell Biology 46: 80–89. DOI: 10.1016/j.biocel.2013.11.001.

Dad S, Rendtorff ND, Tranebjaerg L, et al. (2016) Usher syndrome in Denmark: mutation spectrum and some clinical observations. Molecular Genetics & Genomic Medicine 4 (5): 527–539. DOI: 10.1002/mgg3.228.

Demontis F and Dahmann C (2009) Characterization of the Drosophila ortholog of the human Usher Syndrome type 1G protein sans. PLoS One 4 (3): e4753. DOI: 10.1371/journal.pone.0004753.

Domanico D, Fragiotta S, Cutini A, Grenga PL and Vingolo EM (2015) Psychosis, mood and behavioral disorders in Usher Syndrome: review of the literature. Medical Hypothesis, Discovery and Innovation in Ophthalmology 4 (2): 50–55.

Dyka FM, Boye SL, Chiodo VA, Hauswirth WW and Boye SE (2014) Dual adeno‐associated virus vectors result in efficient in vitro and in vivo expression of an oversized gene, MYO7A. Human Gene Therapy Methods 25 (2): 166–177. DOI: 10.1089/hgtb.2013.212.

Ebermann I, Phillips JB, Liebau MC, et al. (2010) PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. Journal of Clinical Investigation 120 (6): 1812–1823. DOI: 10.1172/JCI39715.

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 (Pt 20): 4593–4603. DOI: 10.1242/jcs.02636.

Fettiplace R and Kim KX (2014) The physiology of mechanoelectrical transduction channels in hearing. Physiological Reviews 94 (3): 951–986. DOI: 10.1152/physrev.00038.2013.

Giese A, Riazuddin S and Ahmed ZM (2013) Usher and Bardet‐Biedl syndrome proteins: new pieces in the planar cell polarity puzzle. Inner Ear Development and Hearing loss 3: 47–65. ISBN 978-1-62417-011-9.

Giese APJ, Tang YQ, Sinha GP, et al. (2017) CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nature Communications 8 (1): 43. DOI: 10.1038/s41467-017-00061-1.

Gregory FD, Pangrsic T, Calin‐Jageman IE, Moser T and Lee A (2013) Harmonin enhances voltage‐dependent facilitation of Cav1.3 channels and synchronous exocytosis in mouse inner hair cells. Journal of Physiology 591 (13): 3253–3269. DOI: 10.1113/jphysiol.2013.254367.

Hu QX, Dong JH, Du HB, et al. (2014) Constitutive Galphai coupling activity of very large G protein‐coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein. Journal of Biological Chemistry 289 (35): 24215–24225. DOI: 10.1074/jbc.M114.549816.

Isgrig K, Shteamer JW, Belyantseva IA, et al. (2017) Gene therapy restores balance and auditory functions in a mouse model of Usher Syndrome. Molecular Therapy 25 (3): 780–791. DOI: 10.1016/j.ymthe.2017.01.007.

Jansen F, Kalbe B, Scholz P, et al. (2016) Impact of the Usher syndrome on olfaction. Human Molecular Genetics 25 (3): 524–533. DOI: 10.1093/hmg/ddv490.

Jayakody SA, Gonzalez‐Cordero A, Ali RR and Pearson RA (2015) Cellular strategies for retinal repair by photoreceptor replacement. Progress in Retinal and Eye Research 46: 31–66. DOI: 10.1016/j.preteyeres.2015.01.003.

Kremer H, van Wijk E, Marker T, Wolfrum U and Roepman R (2006) Usher syndrome: molecular links of pathogenesis, proteins and pathways. Human Molecular Genetics 15 Spec No 2: R262–R270. DOI: 10.1093/hmg/ddl205.

Lefevre 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 (8): 1427–1437. DOI: 10.1242/dev.012922.

Lenassi E, Robson AG, Luxon LM, Bitner‐Glindzicz M and Webster AR (2015) Clinical heterogeneity in a family with mutations in USH2A. JAMA Ophthalmology 133 (3): 352–355. DOI: 10.1001/jamaophthalmol.2014.5163.

Liquori A, Vache C, Baux D, et al. (2016) Whole USH2A gene sequencing identifies several new deep intronic mutations. Human Mutation 37 (2): 184–193. DOI: 10.1002/humu.22926.

Lu B, Wang S, Francis PJ, et al. (2010) Cell transplantation to arrest early changes in an ush2a animal model. Investigative Ophthalmology & Visual Science 51 (4): 2269–2276. DOI: 10.1167/iovs.09-4526.

Maerker 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 (1): 71–86. DOI: 10.1093/hmg/ddm285.

Mathur P and Yang J (2015) Usher syndrome: hearing loss, retinal degeneration and associated abnormalities. Biochimica et Biophysica Acta 1852 (3): 406–420. DOI: 10.1016/j.bbadis.2014.11.020.

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 (24): 6478–6488. DOI: 10.1523/JNEUROSCI.0342-07.2007.

Nagel‐Wolfrum K, Moller F, Penner I and Wolfrum U (2014) Translational read‐through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in‐frame nonsense mutations. Visual Neuroscience 31 (4–5): 309–316. DOI: 10.1017/S0952523814000194.

Nakanishi H, Ohtsubo M, Iwasaki S, et al. (2010) Hair roots as an mRNA source for mutation analysis of Usher syndrome‐causing genes. Journal of Human Genetics 55 (10): 701–703. DOI: 10.1038/jhg.2010.83.

Overlack N, Kilic D, Bauss K, et al. (2011) Direct interaction of the Usher syndrome 1G protein SANS and myomegalin in the retina. Biochimica et Biophysica Acta 1813 (10): 1883–1892. DOI: 10.1016/j.bbamcr.2011.05.015.

Overlack N, Goldmann T, Wolfrum U and Nagel‐Wolfrum K (2012) Gene repair of an Usher syndrome causing mutation by zinc‐finger nuclease mediated homologous recombination. Investigative Ophthalmology & Visual Science 53 (7): 4140–4146. DOI: 10.1167/iovs.12-9812.

Pan B, Askew C, Galvin A, et al. (2017) Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nature Biotechnology 35 (3): 264–272. DOI: 10.1038/nbt.3801.

Phillips JB, Blanco‐Sanchez B, Lentz JJ, et al. (2011) Harmonin (Ush1c) is required in zebrafish Muller glial cells for photoreceptor synaptic development and function. Disease Models & Mechanisms 4 (6): 786–800. DOI: 10.1242/dmm.006429.

Reiners J, Marker T, Jurgens K, Reidel B and Wolfrum U (2005a) Photoreceptor expression of the Usher syndrome type 1 protein protocadherin 15 (USH1F) and its interaction with the scaffold protein harmonin (USH1C). Molecular Vision 11: 347–355.

Reiners J, van Wijk E, Marker T, et al. (2005b) Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2. Human Molecular Genetics 14 (24): 3933–3943. DOI: 10.1093/hmg/ddi417.

Reiners J, Nagel‐Wolfrum K, Jurgens K, Marker T and Wolfrum U (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 (1): 97–119. DOI: 10.1016/j.exer.2005.11.010.

Schietroma C, Parain K, Estivalet A, et al. (2017) Usher syndrome type 1‐associated cadherins shape the photoreceptor outer segment. Journal of Cell Biology 216 (6): 1849–1864. DOI: 10.1083/jcb.201612030.

Seiler C, Finger‐Baier KC, Rinner O, et al. (2005) Duplicated genes with split functions: independent roles of protocadherin15 orthologues in zebrafish hearing and vision. Development 132 (3): 615–623. DOI: 10.1242/dev.01591.

Slijkerman RW, Vache C, Dona M, et al. (2016) Antisense oligonucleotide‐based splice correction for USH2A‐associated retinal degeneration caused by a frequent deep‐intronic mutation. Molecular Theraphy – Nucleic Acids 5 (10): e381. DOI: 10.1038/mtna.2016.89.

Sorusch N, Bauss K, Plutniok J, et al. (2017) Characterization of the ternary Usher syndrome SANS/ush2a/whirlin protein complex. Human Molecular Genetics 26 (6): 1157–1172. DOI: 10.1093/hmg/ddx027.

Talcott KE, Ratnam K, Sundquist SM, et al. (2011) Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment. Investigative Ophthalmology & Visual Science 52 (5): 2219–2226. DOI: 10.1167/iovs.10-6479.

Toms M, Bitner‐Glindzicz M, Webster A and Moosajee M (2015) Usher syndrome: a review of the clinical phenotype, genes and therapeutic strategies. Expert Review of Ophthalmology 10 (3): 241–256. DOI: 10.1586/17469899.2015.1033403.

Tucker BA, Mullins RF, Streb LM, et al. (2013) Patient‐specific iPSC‐derived photoreceptor precursor cells as a means to investigate retinitis pigmentosa. eLife 2: e00824. DOI: 10.7554/eLife.00824.

Vache C, Besnard T, Blanchet C, et al. (2010) Nasal epithelial cells are a reliable source to study splicing variants in Usher syndrome. Human Mutation 31 (6): 734–741. DOI: 10.1002/humu.21255.

Vijayakumar S, Depreux FF, Jodelka FM, et al. (2017) Rescue of peripheral vestibular function in Usher syndrome mice using a splice‐switching antisense oligonucleotide. Human Molecular Genetics 26 (18): 3482–3494. DOI: 10.1093/hmg/ddx234.

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 (5): 751–765. DOI: 10.1093/hmg/ddi490.

Zallocchi M, Meehan DT, Delimont D, et al. (2012) Role for a novel Usher protein complex in hair cell synaptic maturation. PLoS One 7 (2): e30573. DOI: 10.1371/journal.pone.0030573.

Zallocchi M, Binley K, Lad Y, et al. (2014) EIAV‐based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat. PLoS One 9 (4): e94272. DOI: 10.1371/journal.pone.0094272.

Zou J, Chen Q, Almishaal A, et al. (2017) The roles of USH1 proteins and PDZ domain‐containing USH proteins in USH2 complex integrity in cochlear hair cells. Human Molecular Genetics 26 (3): 624–636. DOI: 10.1093/hmg/ddw421.

Zou J, Luo L, Shen Z, et al. (2011) Whirlin replacement restores the formation of the USH2 protein complex in whirlin knockout photoreceptors. Investigative Ophthalmology & Visual Science 52 (5): 2343–2351. DOI: 10.1167/iovs.10-6141.

Further Reading

Ahmed ZM, Frolenkov GI and Riazuddin S (2013) Usher proteins in inner ear structure and function. Physiological Genomics 45 (21): 987–989.

Peng AW, Salles FT, Pan B and Ricci AJ (2011) Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction. Nature Communications 2: 523.

Slijkerman RW, Song F, Astuti GD, et al. (2015) The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies. Progress in Retinal and Eye Research 48: 137–159.

Williams DS, Chadha A, Hazim R and Gibbs D (2017) Gene therapy approaches for prevention of retinal degeneration in Usher syndrome. Gene Therapy 24 (2): 68–71.

Yang J, Wang L, Song H and Sokolov M (2012) Current understanding of Usher Syndrome Type II. Frontiers in Bioscience 17: 1165–1183.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Slijkerman, Ralph WN, Kremer, Hannie, and van Wijk, Erwin(Nov 2017) Molecular Genetics of Usher Syndrome: Current State of Understanding. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021456.pub2]