Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

Abstract

Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance. Three clinically distinct types of USH have been identified, decreasing in severity from Type 1 to 3, with symptoms of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP), and vestibular dysfunction. There are currently nine confirmed and two suspected USH-causative genes, and a further three candidate loci have been mapped. The proteins encoded by these genes form complexes that play critical roles in the development and maintenance of cellular structures within the inner ear and retina, which have minimal capacity for repair or regeneration. In the cochlea, stereocilia are located on the apical surface of inner ear hair cells (HC) and are responsible for transducing mechanical stimuli from sound pressure waves into chemical signals. These signals are then detected by the auditory nerve fibers, transmitted to the brain and interpreted as sound. Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction. This review summarizes the current knowledge on Usher syndrome with a particular emphasis on mutations in USH genes, USH protein structures, and functional analyses in animal models. Currently, there is no cure for USH. However, the genetic therapies that are rapidly developing will benefit from this compilation of detailed genetic information to identify the most effective strategies for restoring functional USH proteins.

Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia

“…Ciliopathies such as Usher syndrome and cilia damage are reported to affect vestibular system of patients and elderly, here we present data showing that mutation of both hdac6 and sirt2 leads to impaired recovery from balance disruption after stimulation (Burns and Stone, 2017;Whatley et al, 2020). It may be associated with the speculated increase in axoneme fragility of cilia, as non-acetylated microtubules were proven to be more susceptible to mechanical stress (Szyk et al, 2014;Portran et al, 2017, Eshun-Wilson et al, 2019.…”

“…This is detected by cristae cilia in the semi-circular canals in response to movement of the gel-like cupula, in which the kinocilia are embedded and are fully functional as early as 3 weeks of age ( Akella et al, 2010 ; Baxendale and Whitfield, 2016 ). Cilia damage in the inner ear and ciliopathies such as Usher syndrome are shown to affect the vestibular system ( Renga, 2019 ; Whatley et al, 2020 ). Growing evidence links acetylation of tubulin to rigidity and resistance to mechanical stress ( Szyk et al, 2014 ; Portran et al, 2017 , Eshun-Wilson et al, 2019 ).…”

A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene–disease relationships

“…The male infertility field is currently catching up with other fields/disease types with a strong genetic component, such as intellectual disability, neuromuscular disorders and hereditary hearing impairments ( Chiu et al , 2020 ; Markitantova and Simirskii, 2020 ; Whatley et al , 2020 ). The rapid uptake of NGS technologies in the male infertility research field over the past 5–10 years, as well as the development of international consortia to collect and characterise clinical cohorts, is aiding in the transition of findings into clinical practice.…”

Cloud-based genomics pipelines for ophthalmology: reviewed from research to clinical practice

“…Clinical genomics is currently predominantly targeted at specific known or suspected hereditary conditions 37 such as retinitis pigmentosa [38][39][40][41][42][43] and its related syndromic variants, [44][45][46][47] macular dystrophies, [48][49][50] and some metabolic diseases. [51][52][53] These inherited retinal dystrophies account for not only severe visual impairment in young people, but also a huge socioeconomic impact on society.…”