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Introduction
Mammalian vision and hearing necessitate accurate functions of sensory and non-sensory cells. In the inner ear, transcriptome studies of the organ of Corti (OC) revealed the expression of at least 18133 genes in hair and supporting cells, 1 underscoring the complexity of inner ear development and function. Deficits in the development, patterning or maintenance of inner ear sensory epithelia, especially in neurosensory hair cells, result in hearing loss (HL), a highly variable phenotype that affects over 70million children worldwide. HL is either the only consistent phenotype (non-syndromic HL) or occurs as one phenotypic feature of a more complex clinical syndrome. There are over 40 syndromes listed in the OMIM database that affect both the auditory and visual systems. Among them, Usher syndrome (USH) is the most common cause of deaf-blindness in school-age children. 2-4
USH is a neurosensory disorder characterised by partial to total HL, variable vestibular areflexia and vision loss that worsens over time. A molecular diagnosis study suggested a frequency of 1/6000 individuals with USH in the USA. 5 Individuals with USH are often classified as having one of three clinical subtypes. Patients with USH type I (USH1) have profound HL and vestibular dysfunction from birth. In addition, night blindness appears earlier in life than in patients with USH type 2 (USH2), who tend to have less severe HL and normal vestibular function. In a third classification (USH3), the HL and retinitis pigmentosa (RP) are progressive, with variable vestibular dysfunction. To date, 14 loci have been mapped for USH in humans, while the genes for only 11 of these loci have been identified. 6 Although variants in each of these genes can cause USH, some variants of USH genes are associated only with deafness or only with retinitis pigmentosa. 7-14 However, variants in the reported 11 USH genes do not account for all cases of USH.
The proteins encoded by the reported USH genes are present in sensory cells of the inner ear and retina. In vitro and in vivo, multiple molecular interactions have been reported between these USH proteins. 15-18 USH1 and USH2 proteins are thought to be assembled into a complex, with a central scaffold role for the PDZ (PSD-95, Dlg, and ZO-1/2) domain-bearing proteins harmonin (USH1C) and whirlin...