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 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 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. © 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. © 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. © Oxford University Press.


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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.

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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]