Etiology & pathogenesis

Causative genes

The first gene for Usher syndrome was discovered in 1995. At present, more than 150 pathogenic mutations for the most common molecular forms USH1B and USH2A have been identified. In all genes implicated in the etiology of Usher syndrome, the disease causing mutations include missense, nonsense, frameshift, splice-site as well as deletions distributed across nearly all exons.

Usher syndrome type 1 is genetically heterogeneous. On the basis of the mutations in genes at five different loci, it is subdivided into USH1B (OMIM 276900), USH1C (OMIM 276904), USH1D (OMIM 601067), USH1F (OMIM 602083), and USH1G (OMIM 606943) (Table 1). Two additional loci associated with Usher syndrome type 1 have been mapped at 21q21 (USH1E, OMIM 602097) and 15q22-q23 (USH1H, OMIM 612632). The USH1A locus does not exist; six of the nine families from the Bressuire region of France originally reported to map at this locus have been found to have mutations in MYO7A (USH1B).

Usher syndrome type 2 is also subdivided into subtypes: USH2A (OMIM 276901), USH2B (it has recently been shown that USH2B locus at chromosome 3p23-24.2 does not exist), USH2C (OMIM 605472, formerly USH2B), and USH2D (OMIM 611383), (Table 1). Mutations in USH2A (USH2A), GPR98/VLGR1 (USH2C) and WHRN (USH2D) account for approximately 80%, 15% and 5% of USH2 cases, respectively.

Mutations in at least two loci have been implicated in Usher syndrome type 3 (OMIM 276902), but USH3A is the only gene identified so far.

Genotype/phenotype correlations

Overlapping and atypical presentations have been described for all three types of Usher syndrome. For example, some mutations in USH2A and USH3 do not give rise to both blindness and deafness, but isolated RP only. Cases of nonsyndromic (isolated) deafness, either recessive or dominant, have been linked to specific (missense or leaky splice site) mutations in some USH1 genes: USH1B, USH1C, USH1D, USH1F. Some mutations in USH2 genes are causative for isolated deafness (WHRN), or isolated RP (USH2A), or atypical USH. Mutations in SANS can also result in atypical Usher syndrome (both missense and deletion mutations). All the mutations in USH genes responsible for isolated deafness or RP reported so far are missense or leaky splice site mutations.

Genotype-phenotype correlations have been found for three of the USH1 genes, USH1G, CDH23 and PCDH15. It has recently been shown that the primary eye defect associated with mutations in MYO7A (USH1B), PCDH15 (USH1F), USH2A (USH2A) and VLGR1 (USH2C) is the photoreceptor degeneration rather than a retinal pigment epithelium or a synaptic defect. Mutations in WHRN have also been reported in several families with recessive nonsyndromic hearing impairment (DFNB31).

Physiological and pathophysiological aspects of the combined hearing and vision loss in Usher syndrome

Pathophysiology of Usher syndrome is complex and still not completely understood. It is, however, well established that the hair cells and photoreceptor cells, which share common structural and functional characteristics, are the primary targets of the hearing and visual deficits, respectively. The cochlear defect of Usher syndrome types 1 and 2 occurs in utero, before the 12th and the 25th week in the inner hair cells (IHC), and the outer hair cells (OHC), respectively. So far, nothing is known on USH3. Conversely, the retinal defect develops in the postnatal development period.

The inner ear consists of two sensory organs: the vestibule (the balance organ) and the cochlea (the hearing organ) (Figure 1).
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Structure of human ear (Encyclopedia Britannica Online:

The auditory sensory epithelium, termed the organ of Corti, is housed in the membranous labyrinth (known as cochlear duct). The organ Corti contains two types of transducer cells that are involved in the sound processing in the cochlea: IHC, which are responsible for the neurotransmitter release and are considered to be purely sensory, and OHC, which play sensorymotor role and are responsible for the amplification of the sound-evoked vibrations.

Each IHC or OHC is crowned by a unique array of thick and stiff microvilli filled with hundreds of actin crosslinked filaments, termed stereocilia, that project a few micrometres from their apical surface and form the so-called hair bundle. The hair bundle is made up of 20-300 stereocilia and a single genuine cilium, the kinocilium (only transient in the cochlear sensory cells during development). The stereocilia of OHC hair bundles are arranged in three to four rows of increasing heights toward the kinocilium, forming a distinct "V"-shaped (or W-shaped) staircase, where the kinocilium is located at the vertex of the V. IHC hair bundles have a flatter, slightly curved profile. The role of the hair bundle is to capture and convert nanometer stereocilia displacements induced by sound waves into measurable membrane potential changes, a process known as mechanoelectrical transduction.

Two types of links interconnect adjacent stereocilia in the mature hair bundle: tip-links (that connect the tip of each stereocilium to the side of the nearest taller stereocilium) and horizontal top connectors (lateral links that couple adjacent stereocilia both within and between rows). The tip links are oriented along the hair bundle's axis of mechanosensitivity. They are believed to gate the mechanotransducer channels of the hair cells. During development, different lateral links connect the growing stereocilia to each other and the kinocilium to the adjacent stereocilia of the tallest row. They include the transient lateral links (distributed extensively over the entire surface of the emerging stereocilia; disappear after birth), the kinociliary links (they connect the kinocilium to the immediately adjacent stereocilia; disappear after birth) and the ankle links (distributed around the basal region of the hair bundle at postnatal day 2 (P2); persisting up to P9-P11). The horizontal top connectors appear relatively late during development and persist into adulthood. The transient links and top connectors are critically involved in the cohesion of the growing and mature hair bundle.

Usher proteins

The disease-causing genes in Usher syndrome encode proteins of different classes. They are located in the hair bundle and synaptic area of hair cells in the inner ear, and in periciliary and synaptic areas of photoreceptor cells in the retina. Mutations in the different Usher genes can lead to a broad spectrum of phenotypes in the ear and eye. Recent reports provide evidence for the existence of an integrated Usher protein network(s?) in both the inner ear and the retina. Numerous direct interactions between USH proteins have been found in vitro ("USH protein interactome"), many of which are likely to occur also in vivo, within dynamic molecular complexes. These complexes play essential roles in the morphogenesis of the hair bundle, in the catalycal processes of photoreceptor cells and in the synaptic processes of both cell types.

The causative genes for Usher syndrome type 1 have been shown to encode a set of proteins named USH1 proteins: myosin VIIa, cadherin 23, protocadherin 15, harmonin and sans. These proteins are components of different stereocilia links and together form supramolecular complexes.All USH1 proteins are present in the hair bundle during its early development, playing a key role in this process. They are also key components of the mechanoelectrical transduction machinery. At clinical level, the phenotype of USH1 patients caused by mutations in different USH1 genes can not be distinguished, suggesting that the USH1 proteins may be implicated in the same cellular function(s). The early cochlear hair bundle anomalies associated with USH1 gene defects alone account for the congenital deafness of USH1 patients.

Myosin VIIa (molecular motor that uses actin filaments as a substrate to generate force and movements in response to the hydrolysis of ATP) is widely distributed throughout the hair cell and may be concentrated in some particular regions of the hair bundle. Cadherin-23 and protocadherin-15 are transmembrane adhesion proteins, members of the Ca2+-dependent cell-cell adhesion molecule superfamily. These two USH1 proteins form the tip links (that gate the hair cells mechanoelectrical transduction channels) and the transient lateral links (that play a key role in the development of a unitary properly oriented "V"-shaped hair bundle). Harmonin is a PDZ domain-containing scaffolding protein. Harmonin b-isoform most likely mediates the attachement of the tip link protein cadherin-23 to the actin cytoskeleton (Figure 2). The interaction between USH1 proteins suggest that cadherin-23 is anchored to the stereociliary actin filaments via harmonin b and that myosin VIIa exerts tension on the early hair bundle links composed of cadherin-23 and protocadherin-15. Sans is a scaffolding protein with ankyrin repeats that belongs to the tip-link molecular complex and is required for the maintenance of the tip-links.

The USH2A and USH2C genes code for the transmembrane proteins usherin and Vlgr1 (very large G protein-coupled receptor-1), respectively. The USH2D gene encodes whirlin (Figure 3), a PDZ domain-containing protein, which is the closest homolog of harmonin. These three proteins are colocated at the stereocilia base during development, up to almost the final maturation of the hair bundle. Vlgr1, usherin and whirlin have been suggested to be components of the ankle link molecular complex. In cochlear hair cells, usherin has also been detected in the synaptic region. Whirlin is also present at the stereocilia tips, where it persists at mature stages.

In the retina, USH protein network is localized at the interface of the inner segment and the light sensitive outer segment of rod and cone vertebrate photoreceptor cells termed connecting cilium. The connecting cilium has an essential role in the transport of phototransduction proteins and disc membrane lipids from the inner segment (where they are synthesized) to the outer segment. The cooperation of the network members may contribute to the regulation of cargo transfer from inner segment transport carriers to the ciliary transport system. Dysfunction or absence of any of the proteins in the ciliary-periciliary USH protein network may lead to the disruption of the entire network function and cause retinal degeneration.

USH mouse models have shown that hair cells are the primary target cells of the hearing deficit, and that the latter results from abnormal development of the hair bundle (disorganized stereocilia, and in some cases fragmented and misoriented hair bundles). In USH1 mouse models, only the hearing and balance defects typical of the human USH1 have been reproduced, but not the RP; some electrophysiological anomalies of the retina, however, have been reported in some of the mutants, suggesting a defect in the photoreceptor cells. Contrary to earlier studies, shaker-1 mice that have mutant Myo7a (USH1B animal model) was recently shown to possess a robust retinal phenotype. A knock-in mouse containing the human USH1C c.216G>A mutation that reproduce the auditory and visual defects found in Acadian Usher I patients has recently been created. In USH2 mouse models, hearing impairment and photoreceptor degeneration characteristic for human USH2 have been reproduced.

Inheritance and genetic counseling

Usher syndrome is inherited in an autosomal recessive pattern. The parents of a child with this condition each carry one copy of the mutated gene, but they are typically asymptomatic. Each subsequent pregnancy will have a 25% risk of resulting in affected child, a 50% risk for an unaffected child who is a carrier of one copy of the mutated gene, and a 25% chance for unaffected child who is not a carrier of the mutation.

Prenatal testing for pregnancies at increased risk for some forms of Usher syndrome may be available on a clinical basis, if the disease-causing mutations have been identified in the family. The hearing of at-risk sibs should be assessed as soon after birth as possible. Genetic counseling will allow the parents to prepare the child with Usher syndrome for educational and social needs corresponding to the hearing impairment and progressive loss of sight, and focus on communication skills that will be needed.