Human Molecular Genetics 2006 15(Review Issue 2):R262-R270; doi:10.1093/hmg/ddl205
© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Usher syndrome: molecular links of pathogenesis, proteins and pathways
Hannie Kremer1,*,
Erwin van Wijk1,
Tina Märker4,
Uwe Wolfrum4 and
Ronald Roepman2,3
1 Department of Otorhinolaryngology ,
2 Department of Human Genetics, Radboud University Nijmegen Medical Centre ,
3 Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands and
4 Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany
* To whom correspondence should be addressed at: Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Internal Postal Code 377, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 243610487; Fax: +31 243668752; Email: h.kremer{at}antrg.umcn.nl
Received July 7, 2006; Accepted July 28, 2006
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ABSTRACT
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Usher syndrome is the most common form of deaf-blindness. The
syndrome is both clinically and genetically heterogeneous, and
to date, eight causative genes have been identified. The proteins
encoded by these genes are part of a dynamic protein complex
that is present in hair cells of the inner ear and in photoreceptor
cells of the retina. The localization of the Usher proteins
and the phenotype in animal models indicate that the Usher protein
complex is essential in the morphogenesis of the stereocilia
bundle in hair cells and in the calycal processes of photoreceptor
cells. In addition, the Usher proteins are important in the
synaptic processes of both cell types. The association of other
proteins with the complex indicates functional links to a number
of basic cell-biological processes. Prominently present is the
connection to the dynamics of the actin cytoskeleton, involved
in cellular morphology, cell polarity and cell–cell interactions.
The Usher protein complex can also be linked to the cadherins/catenins
in the adherens junction-associated protein complexes, suggesting
a role in cell polarity and tissue organization. A third link
can be established to the integrin transmembrane signaling network.
The Usher interactome, as outlined in this review, participates
in pathways common in inner ear and retina that are disrupted
in the Usher syndrome.
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INTRODUCTION
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Usher syndrome (MIM nos 276900
[OMIM]
-2, 276905 and 605472) is the
most common form of deaf-blindness with a prevalence of
1/20 000
and represents 50% of the cases with deaf-blindness (
1–
3).
The hearing loss in the patients is sensorineural and most severe
for high frequencies. Loss of vision is due to retinitis pigmentosa
(RP), a progressive retinal degeneration leading to blindness
(
4–
6). Usher syndrome can be associated with vestibular
dysfunction, reduced odor identification and sperm motility
and mental deficiency, cerebral atrophy and ataxia (reviewed
in
4,
7).
Three clinical subtypes of the syndrome are distinguished, mainly on the basis of the severity and progression of the hearing loss and the age of onset of RP (8). Usher syndrome type I (USH1) is the most severe with congenital severe to profound hearing loss and a prepubertal onset of RP. Usher syndrome type II (USH2) is the most common subtype and characterized by congenital moderate to severe hearing loss and onset of RP during or after puberty. Hearing loss is progressive in Usher type III (USH3), and onset of RP is variable. To date, five genes and two loci are known for USH1, two genes for USH2 and one gene and one locus for USH3 (Table 1; reviewed in 7). Mutations in the genes associated with USH1B, C, D, and F are also associated with non-syndromic hearing loss, and mutations in the USH2A gene are the most frequent cause of autosomal recessive RP (9,10) (Table 1; reviewed in 4,7,11).
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USHER PROTEINS: THEIR STRUCTURE AND ISOFORMS
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The proteins encoded by the Usher genes (Fig.
1) are members
of protein classes with very different functions. Myosin VIIa
is a motor protein, harmonin and SANS (scaffold protein containing
ankyrin repeats and SAM domain) are scaffold proteins, cadherin
23 and protocadherin 15 are cell adhesion molecules and USH2A/usherin
(isoform B) and VLGR1b (very large G-coupled protein receptor
isoform b) are transmembrane proteins that could be involved
in outside-in signaling. The protein encoded by the
USH3A gene,
clarin-1, is a member of the vertebrate-specific clarin family
of four-transmembrane-domain proteins (
12).
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Figure 1. Outline of the Usher proteins and their different isoforms. (A) The Usher 1B protein, myosin 7a, consists of a motor head domain, five calmodulin-binding IQ motifs, two FERM domains, two MyTH4 domains and an Src homology 3 (SH3) domain. (B) The USH1C protein, harmonin, of which three different classes of isoforms are identified. All three isoforms consist of two PDZ (PSD95, discs large, ZO-1) domains (PDZ1 and 2) and one coiled-coil domain. In addition, 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). Isoforms A1 and B4 contain a C-terminal class I PDZ binding motif (PBM). (C) Cadherin 23 (USH1D) is represented by three different isoforms. Isoform A is composed of 27 Ca2+-binding extracellular cadherin domains (EC1-27), a transmembrane domain (grey disks) and a short intracellular domain with a C-terminal class I PBM. Isoform B is similar to isoform A, but only contains the last six EC domains. Isoform C only consists of the intracellular domain and C-terminal PBM. (D) Like cadherin 23, the non-classical cadherin protocadherin 15 (USH1F) consists of either 11 (isoform A) or one (isoform B) EC domain, 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 fibronection type III (FN3) domains. In addition to this region, isoform B contains two laminin G (LamG), 28 FN3, a transmembrane domain and an intracellular domain with a C-terminal class I PBM. (G) Isoform B of the very large G-coupled protein receptor, VLGR1 (USH1C), contains a thrombospondin/pentaxin/laminin G-like domain, 35 Ca2+-binding calcium exchanger ß (Calx) domains, seven EAR/EPTP repeats, a seven-transmembrane region and an intracellular domain containing a C-terminal class I PBM. (H) Clarin-1, the USH3A protein, only contains four (isoform A) or one transmembrane (isoform C) domain.
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HARMONIN AND WHIRLIN MEDIATE THE FORMATION OF AN USHER PROTEIN MULTIASSEMBLY COMPLEX
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Mutations in the different Usher genes can lead to a broad spectrum
of phenotypes in the ear and eye, but recent reports provide
evidence for the existence of an integrated Usher protein network
in both the inner ear and the retina (
13–
15) (Fig.
2).
In this network, the USH1 and USH2 proteins are thought to be
assembled in a multiprotein scaffold, with a central role for
the PDZ domain containing protein homologs, harmonin and whirlin.
Therefore, the gene encoding whirlin,
DFNB31, was recently proposed
as a functional candidate gene for Usher syndrome (
15). In most
of the cases, these two protein homologs bind with one or more
of their PDZ domains to either a C-terminal class I PDZ binding
motif (PBM; -X[ST]X[VIL]
–COOH (
16) or to internal PDZ
binding domains of their interacting partners. To date, all
proteins in this network that are associated with USH1 (myosin
VIIa, cadherin 23, SANS and protocadherin 15) or type 2 (USH2A
and VLGR1b) have been described to interact with both harmonin
and whirlin (Fig.
2). Binding of VLGR1b (
14,
15), usherin/USH2A
isoform B (
14,
17) and protocadherin 15 (
18) to the PDZ domains
of whirlin and/or harmonin was found to be strictly dependent
on their C-terminal class I PBM, whereas binding of cadherin
23 (
19) involves both a class I C-terminal PBM and an internal
PBM resembling the PBM of RIL (
20). As myosin VIIa does not
contain a C-terminal PBM, its binding relies on one or more
putative internal PBMs (
21). Myosin XVa (
22) and SANS (
13) do
contain a conserved C-terminal class I PBM, but their binding
to harmonin and/or whirlin is not visibly affected by deletion
of this motif, indicating that also one or more (putative) internal
PBMs are involved in the binding. SANS (
13) and protocadherin
15 (
23) were also found to interact with myosin VIIa.
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Figure 2. The Usher protein network. All identified protein–protein interactions are indicated. Red colored boxes indicate association with Usher syndrome, blue color indicates association with isolated 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).
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Although harmonin and whirlin share many protein partners, different
partners have been identified for either harmonin [NBC3 (
14,
15),
MCC2 (
24), harp (
25), DOCK4 (
26), actin (
21) and ß-catenin
(
7,
25)] or whirlin [NGL1 (
22), CASK (
27) and myosin XVa (
22,
28)],
indicating that their binding repertoire is not fully overlapping
(Fig.
2). It is likely that at least a subset of these
will also bind to the other protein homolog, as in many of these
proteins a conserved class I PBM can be identified. However,
although the PDZ domains of whirlin and harmonin are quite homologous
(
15), differences in protein–protein interactions have
been found. Both PDZ1 and 2 domains of whirlin were found to
bind to USH2A isoform b (
15), whereas this protein only binds
to PDZ1 of harmonin (
14). Furthermore, the harmonin interactor
NBC3, binding to PDZ1 of harmonin, was found not to interact
with whirlin (
15).
Besides these protein–protein interactions, many of the proteins in this network, such as harmonin (13,19), whirlin (22), SANS (13), NGL-1 (22), RI
of PKA (29) and PHR1 (30), have been shown to form homodimers. The dimerization properties of myosin VIIa are under debate (31–33). In addition, different isoforms derived from splicing variation have been identified for many of the proteins, including the central organizers whirlin and harmonin, thus increasing the complexity of this interactome. This network very likely will expand in the future. For example, the Usher type III protein clarin-1, in line with the type I and type II proteins, is expected to belong to the network (12).
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LOCALIZATION OF THE USHER PROTEIN COMPLEX IN INNER EAR AND RETINA
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The Usher protein complex in inner ear and retina seems to have
its major function in the neurosensory cells, respectively,
in the hair cells and photoreceptor cells (Fig.
3). In
the inner ear, hair bundles are located at the apical surface
of both the auditory and vestibular hair cells. The displacement
of the hair bundle by a sound wave opens the mechanotransduction
channel at the tip of the stereocilia, which initiates the signaling
cascade for sound perception (
34,
35). The hairs, or stereocilia,
develop from microvilli and have a stiff core of parallel actin
filaments anchored in the cuticular plate, a meshwork of horizontal
actin filaments beneath the apical cell membrane. The kinocilium,
a true cilium, is connected to the developing stereocilia bundle
and essential for its orientation. The morphogenesis of hair
cells is reviewed in (
36,
37). The major sites of colocalization
of Usher proteins in the inner ear are the stereocilia and the
synaptic regions of hair cells (
13–
15,
19,
21,
23). In addition,
the spiral ganglion neurons harbor several of the Usher proteins
such as USH2A (
15), protocadherin 15 (
38) and USH3A (
12). In
the cuticular plate, harmonin and myosin VIIa are co-expressed
(
21,
39–
41). Cadherin 23 is also found in Reissner's membrane
(
42,
43) and SANS, protocadherin 15 and USH2A in the supporting
cells (
13,
17,
38).
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Figure 3. Diagram 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 kept together by the tip links, horizontal links and ankle links. The stereocilia are anchored in the actin-rich cuticular plate. The kinocilium is located lateral to the largest stereocilium and is formed from the basal body. The synaptic junction between hair cell, efferent and afferent neurons at the basal side of the hair cell, contains 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 modified cilium containing the phototransduction proteins, is separated from the inner segment by the connecting cilium. The calycal processes are situated next to 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.
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In the retina, the visual signaling cascade is associated with
disk membranes within the outer segments of the photoreceptor
cells. Its activation leads to a hyperpolarization of photoreceptor
cells and the reduction of neurotransmitter release at their
synapses, located in the outer plexiform layer (OPL) (
44). The
USH proteins colocalize in this synaptic layer (
7,
14,
15,
18,
45),
as well as in the ciliary region between the outer and inner
segments, more particularly in the connecting cilium, and the
calycal processes (Fig.
4) (
14,
15,
41,
46–
48). Protocadherin
15, USH2A and VLGR1 have also been detected in the outer limiting
membrane, the region of adherens junctions (
14,
15) between photoreceptor
cells and Müller glia cells. Myosin VIIa is also located,
although under debate, in the OPL (
7) and in the retinal pigment
epithelium (
48). Harmonin and protocadherin 15 are also present
in the outer segments (
18,
45), and harmonin and SANS were found
to colocalize in the inner segments (
7,
45).
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Figure 4. Subcellular localization of USH2A and whirlin in the ciliary region of photoreceptor cells. Electron micrographs of mouse photoreceptor cells illustrating silver-enhanced immunogold labeling of (A) USH2A and (B) whirlin in longitudinal sections of the outer segment (OS) and the apical inner segment (IS) of a rod photoreceptor cell. Labeling is restricted to the periciliary region in calycal processes (CP) of IS facing the connecting cilium (CC). Scale bars: 0.5 µm.
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THE USHER PROTEIN COMPLEX IN STEREOCILIA DEVELOPMENT
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The phenotype of
shaker, waltzer,
deaf-
circler,
ames waltzer and
Jackson shaker mice, which harbor a mutation in one of the
USH1 genes, indicate that several of the Usher proteins are
essential for the development and cohesion of the stereociliar
bundle of hair cells in both the cochlea and the vestibular
organ (reviewed in
4,
11). During growth and maturation and also
in adulthood, stereocilia maintain their cohesion by fibrous
interstereociliar links and by links with the kinocilium. In
addition, the stereocilia are covered with the cell coat material
during development, also described as shaft connectors, and
at the tip with the tectorial membrane attachment crown. The
type of links in the hair bundle rapidly changes during development
in a species- and hair cell type-specific manner (reviewed in
49). From the earliest stages of stereocilia development in
the outer hair cells of mouse cochlea, transient lateral links
are present that diminish at early postnatal stages when ankle
links appear at the base of the stereocilia. Subsequently, the
latter diminish and horizontal top connectors appear that are
maintained in adulthood. The tip link that connects the tip
of a stereocilium to the shaft of the neighboring taller stereocilium
is present from E17.5 onwards. The general figure that emerges
for the localization of Usher proteins in stereociliar development
is that the large extracellular regions of the transmembrane
proteins cadherin 23, protocadherin 15, USH2A isoform b and
VLGR1b are part of the links that are intracellularly attached
to the scaffold proteins harmonin and/or whirlin. These scaffold
proteins are directly or indirectly (via myosin VIIa, myosin
XV and/or vezatin) connected to the actin core of the stereocilia
[for discussion see also (
11)]. The molecular composition of
the different types of links is being elucidated on the basis
of the spatiotemporal expression, immuno-histochemistry and
immuno-electronmicroscopy. Cadherin 23 has been shown to be
a component of the transient lateral and kinocilial links and,
although still under debate, might be a component of the tip
link (
50–
52). For USH2A and VLGR1, evidence is emerging
that they are components of the ankle links (
17,
53). Protocadherin
15 might also be part of these links, although not essential
(
23). In addition, the myosin VIIa-binding protein vezatin has
been suggested to be associated with the ankle links (
54) and,
interestingly, whirlin appears at the base of the stereocilia
in the period during which ankle links are present (
22). This
suggests that whirlin might be involved in the anchoring of
the ankle links through its association with USH2A and VLGR1
and with myosin VIIa (
15,
17). The actin bundling and stabilization
activity of harmonin b might contribute to the growth of the
stereocilia (
21). The scaffold protein SANS, not present in
stereocilia but in the kinocilium of OHC of P3 mice (
17), might
have a role in anchoring kinociliar links via myosin VIIa.
SANS is mainly concentrated below the cuticular plate in IHCs and in the OHCs, especially below the kinociliar basal body where the cuticular plate is thinner (13). The localization of SANS overlaps with the concentration of vesicles and microtubules in the apical peri- and subcuticular regions including the subkinocilial region (55). Therefore, SANS has been suggested to function in the trafficking of the Usher proteins along microtubules and actin filaments toward the stereocilia and kinocilium (7,11,13). Indeed, in mice defective for SANS or myosin VIIa, harmonin b is absent from the stereocilia and accumulates in the apical region of the hair cells (11,21).
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USHER PROTEINS AT SYNAPTIC REGIONS OF PHOTORECEPTOR AND HAIR CELLS
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All Usher proteins (except for clarin-1) have been shown to
be present in the OPL of the mouse and/or rat retina (
7,
14,
18,
45).
For the inner ear, the localization of Usher proteins at the
synaptic terminals of the neurosensory cells has been less extensively
studied. The presence of harmonin, SANS, USH2A and VLGR1 at
these sites has been reported for both IHCs and OHCs (
13,
14).
Whirlin was demonstrated in the synaptic region of OHCs only
(
15). It has not been sorted out yet whether the USH proteins
function at the pre- or postsynaptic sides of synapses or at
both sides. Also, it remains to be determined whether Usher
proteins function directly in the synaptic ribbon. For whirlin,
this is unlikely because it was only detected in the OHC synaptic
region which only contains ribbon synapses in the apical coil
of the cochlea (
15). Only for
Myo7a mutants, the ultrastructure
of synaptic regions of hair cells, more specifically the ribbon
synapses in IHCs and OHCs, has been investigated and found to
be normal (
40). Thus, we can only speculate about the function
of the Usher protein complex in synapses. Myosin VIIa has been
suggested to have a role in either transporting synaptic molecules
or in endocytosis (
56). Cadherin 23, protocadherin 15, USH2A
and VLGR1, anchored by harmonin, SANS or whirlin, might function
in keeping the synaptic membranes closely apposed by homo- or
heterotypic interaction of their large extracellular regions
(
7,
15,
57). In addition, VLGR1, being a G-coupled protein receptor,
might be involved in signaling and in ion homeostasis because
of its Ca
2+-binding calcium exchanger ß-domains.
PDZ proteins are known to be a major component of excitatory synapses, and several members of the PSD-95 (postsynaptic density protein 95) family of PDZ proteins are differentially expressed in the synaptic regions of inner ear hair cells and photoreceptors (58,59). Whether harmonin, whirlin and SANS are specifically involved in the anchoring of Usher proteins in the synaptic region or also have a scaffolding function for other components of the large network of synaptic proteins, such as several types of Ca2+- and K+-channels or neurotransmitter receptors, remains to be determined. The association and colocalization of harmonin and NBC3 at the synaptic regions of both hair cells and photoreceptor cells suggest this to be the case (14). As PDZ protein scaffolds are also emerging as regulators of dynamic synaptic processes controlling its strength, structure and plasticity (reviewed in 60), a harmonin/whirlin organized scaffold might be involved in similar processes. They might also play a role in the transport of cargo vesicles to the synapse by contacting molecular motors, myosin VIIa, for example, as suggested for other PDZ proteins (60), and comparable with the function that has already been suggested for SANS and myosin VIIa in the sub/pericuticular region.
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THE USHER PROTEIN COMPLEX FUNCTIONS IN THE CALYCAL PROCESSES OF PHOTORECEPTOR CELLS
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Cadherin 23 and the ankle link antigen, recently shown to be
VLGR1 (
46,
47,
53), were previously described to be localized
in the fibrous links that connect the calycal processes of photoreceptor
cells to the connecting cilium membrane and outer segments.
The calycal processes are microvilli-like extensions from the
apical region of inner segments that surround the basis of the
outer segments and actin filaments extend into these calycal
processes (
61,
62). Analogous to the stereociliar links, VLGR1
and also USH2A and whirlin are located at the more proximal
part of the calycal processes in the so-called periciliary ridge
complex of mammalian photoreceptor cells (Fig.
4 and Märker
et al., manuscript in preparation). This periciliary ridge
region corresponds to the docking side of post-Golgi vesicles
(e.g. opsin transport carriers), which are translocated through
the inner segment to the apical membrane, for further delivery
through the connecting cilium to the outer segment (reviewed
in
63). In contrast, recent investigations indicate the localization
of protocadherin 15 more distally in the calycal processes (Märker
and Wolfrum, unpublished observations). Myosin VIIa was not
reported to be present in these structures, but myosin IIIa
might be its functional homolog there (
64). Mutations in the
MYO3A gene cause hearing loss, but not visual impairment (
65).
Not much is known about the function of the calycal processes,
but a role in rod outer segment disk morphogenesis has been
suggested (
66). The localization of several members of the Usher
protein complex in the fibrous links associated with the calycal
processes suggests a structural role of the complex analogous
to that in the stereocilia.
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THE USHER PROTEIN COMPLEX AT CROSSROADS OF CELLULAR FUNCTION
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Many of the reported interactions at different sites in the
inner ear and retina have functional implications for these
organs. Some important links need to be highlighted that connect
the Usher complex to basic cellular pathways. These are indicative
of a conserved role in the eye and the ear. Very prominently
present in the complex are multiple links to the actin cytoskeleton,
i.e. through binding of actin to harmonin (
21), to myosin XVa
(
67), to the USH2A interactors fibronectin (
68,
69) and integrin
(
70), and to myosin VIIa (
33,
71) as well as to its interactors
MyRIP/Slac2-c (
72,
73) and KEAP1 (
74,
75). The actin cytoskeleton
is essential in cellular morphology, polarity, motility and
in cell-to-cell interaction (
76). Actin renewal in stereocilia
was found to follow a treadmill mechanism, shaping the functional
architecture of the stereocilia bundle and thus regulating its
length (
67), a process that also involves the unconventional
myosins VI, VIIa, XVa and X (
77). Similar actin- and myosin-guided
processes are also essential in neuronal morphogenesis and structural
plasticity of adult neurons, and these processes are subserved
by signaling of the Rho family of small GTPases (
78). This signaling
was recently also connected to the Usher interactome through
the harmonin interactor DOCK4, a guanine nucleotide exchange
factor (GEF) for Rho GTPase and a potent Rac activator (
26).
The presence of the Usher protein complex in the photoreceptor
synaptic region of the retina, the OPL, and in the ribbon synapses
in the inner ear (
14,
15,
18,
45) is fully in line with these findings.
Besides playing an important role in the architecture of the actin cytoskeleton, the Usher protein network can also be connected to the cadherins/catenins in the adherens junction-associated protein complexes. Although the direct interaction of the members of the cadherin superfamily in this complex, protocadherin 15 and cadherin 23, has not yet been demonstrated, harmonin (7,25) and the USH2A interactor integrin (79,80) were found to interact with ß-catenin, whereas vezatin was found to link myosin VIIa to the cadherins/catenins in the adherens junctional protein complexes in inner ear hair bundles (54). In view of the recently revised model of cadherin–catenin–actin association (81,82), the Usher proteome may be involved in this process in multiple ways, both by participating in the actin renewal, as described before, and by providing the direct actin links with other junction proteins, which could be one or more of the transmembrane proteins present in the network. The stimulation of the formation of adherens junctions by DOCK4 activation of the Rap GTPase (83) is fully in line with such a connection. The identification of the transmembrane proteins USH2A and VLGR1, as well as whirlin at the actin-rich outer limiting membrane of the retina (15), the site of the photoreceptor-Müller cell junctions, would match with a role of the Usher protein complex in the adherens junctions and associated processes in the retina. The binding of USH2A to fibronectin, integrin (84) and collagen IV (85) would enhance the actin–catenin–cadherin connection and anchor it to the extracellular matrix.
The presence of integrin in the network would also provide means for bidirectional signaling through the cell membrane as a response to adhesive ligands (86), as well as a role in Rho signaling-directed microtubule stabilization (87). Although it is unknown what the specific implications are of the link of the Usher protein complex with the microtubuli, it physically links to this important cytoskeletal structure through binding to the microtubule associated protein-2B (88). Its interacting motor protein, myosin VIIa, has also been shown to enable opsin transport through the microtubuli (89,90) and although this was indicated to be an actin-based transport mode (89), cooperation between actin and microtubule-based motor proteins has been described (91).
Finally, already in the absence of any knowledge on molecular defects in Usher syndrome, it was suggested to be due to defects in cilia structure or function (92), and RP is a characteristic of several of the disorders, such as Bardet-Biedl syndrome, which are caused by defects in proteins localized to cilia or basal bodies (93). Recently, it was shown that disruption of several of the ciliary proteins involved in Bardet-Biedl syndrome perturbs planar cell polarity illustrated by the disrupted orientation of the stereocilia bundles and a genetic interaction between BBS genes and the planar cell polarity gene Vangl2 in mouse and zebrafish. In accordance with this, the Vangl2 protein was found to be present in the basal body and axoneme of ciliated cells (94). Some signs of disturbed planar cell polarity have also been described for mice that have a mutation in one of the Usher genes, and cadherin 23, probably isoform c, is present in the basal body/centrosomes of cochlear and vestibular hair cells already during development and in the greater epithelial ridge of the cochlea (42). Preliminary data indicate that also other Usher proteins are present in the basal body, in this case, the basal body of the connecting cilium. The localization of whirlin, protocadherin 15, USH2A and VLGR1 in the outer limiting membrane (15,18) also suggests a connection of the Usher protein complex to apico-basal cell polarity. This might be supported by the localization of members of the crumbs protein family in the basal body of hair cell kinocilia and the presence of other apico-basal cell polarity determinants in cilia (95).
In summary, the outline of the Usher interactome, as shown in this review, reveals important common denominators that could account for the common phenotypic characteristics in the inner ear and retina of Usher syndrome patients. In addition, it points out that the genes encoding different partners in the complex are, by association, candidate genes for Usher syndrome, neurosensory deafness and retinal degeneration.
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ACKNOWLEDGEMENT
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The authors wish to thank Frans Cremers for critical comments
on the manuscript.
Conflict of Interest statement. None declared.
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ABSTRACT
INTRODUCTION