Usher protein functions in hair cells and photoreceptors

Abstract

The 10 different genes associated with the deaf/blind disorder, Usher syndrome, encode a number of structurally and functionally distinct proteins, most expressed as multiple isoforms/protein variants. Functional characterization of these proteins suggests a role in stereocilia development in cochlear hair cells, likely owing to adhesive interactions in hair bundles. In mature hair cells, homodimers of the Usher cadherins, cadherin 23 and protocadherin 15, interact to form a structural fiber, the tip link, and the linkages that anchor the taller stereocilia's actin cytoskeleton core to the shorter adjacent stereocilia and the elusive mechanotransduction channels, explaining the deafness phenotype when these molecular interactions are perturbed. The conundrum is that photoreceptors lack a synonymous mechanotransduction apparatus, and so a common theory for Usher protein function in the two neurosensory cell types affected in Usher syndrome is lacking. Recent evidence linking photoreceptor cell dysfunction in the shaker 1 mouse model for Usher syndrome to light-induced protein translocation defects, combined with localization of an Usher protein interactome at the periciliary region of the photoreceptors suggests Usher proteins might regulate protein trafficking between the inner and outer segments of photoreceptors. A distinct Usher protein complex is trafficked to the ribbon synapses of hair cells, and synaptic defects have been reported in Usher mutants in both hair cells and photoreceptors. This review aims to clarify what is known about Usher protein function at the synaptic and apical poles of hair cells and photoreceptors and the prospects for identifying a unifying pathobiological mechanism to explain deaf/blindness in Usher syndrome.

Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells

“…2 To date, there are 13 loci and 10 genes known to be involved in the three clinical types of Usher syndrome. [3][4][5][6] Mutations in six of these genes, MYO7A, 7-10 CDH23, 11,12 PCDH15, 13,14 WHRN, 15,16 SANS 17 and CIB2, 4 can lead to either Usher syndrome or autosomal recessive NSHI (arNSHI). Mutations in USH2A can lead to either Usher syndrome or nonsyndromic retinitis pigmentosa.…”

Molecularly and structurally distinct synapses mediate reliable encoding and processing of auditory information

“…Loss of function mutations of the pore-forming alpha subunit of the Ca V 1.3 channel lead to deafness in humans (Baig et al, 2011). Usher syndrome is an autosomal recessive sensory disorder resulting in blindness and deafness (overview in Cosgrove and Zallocchi, 2014). Many proteins were shown to cause mutations in the USHER gene locus inducing Usher disease of different types (Grati et al, 2012).…”

A Founder Mutation inMYO7AUnderlies a Significant Proportion of Usher Syndrome in Indigenous South Africans: Implications for the African Diaspora

“…To date, six genes have been associated with USH type 1, namely CDH23, CIB2, MYO7A, PCDH15, USH1C, and USH1G. 4 Usher syndrome type 2 is less severe, characterized by congenital hearing loss that is moderate to severe, with normal vestibular functioning and a later RP onset. Mutations in three genes, namely DFNB31, GRP98, and USH2A, cause type 2 USH.…”

“…Two genes are associated with USH type 3, namely CLRN1 2 and HARS, 5 with a third gene (ABHD12) being associated with a variant of this subtype. 6 A number of USH protein interactions (or interactomes) have been reported, 4,7 which function in the development and maintenance of stereocilia hair bundles of the inner ear and which also colocalize in the synaptic layer, connecting cilium and the calyceal processes of the photoreceptors of the retina. The exact function of these protein interactomes is not known, as mouse models (of mutated USH genes) have little or no retinal phenotype, but they may have a role in protein trafficking between the inner and outer segments of the photoreceptors, as well as synaptic function of these sensory neurons.…”

“…The exact function of these protein interactomes is not known, as mouse models (of mutated USH genes) have little or no retinal phenotype, but they may have a role in protein trafficking between the inner and outer segments of the photoreceptors, as well as synaptic function of these sensory neurons. 4 Due to the genetic and clinical heterogeneity, the large size of the genes, and multiple isoforms underlying the syndrome, identifying the molecular basis of USH in affected South African families using traditional candidate gene screening methods has been challenging. Technologic advances, such as the development of microarrays and next generation sequencing, have significantly improved the turnaround time and success rates of genetic mutation screening for inherited retinal degenerative diseases.…”