Pathogenesis and Treatment of Usher Syndrome Type IIA

Abstract

Usher syndrome (USH) is the most common form of deaf-blindness, with an estimated prevalence of 4.4 to 16.6 per 100,000 people worldwide. The most common form of USH is type IIA (USH2A), which is caused by homozygous or compound heterozygous mutations in the USH2A gene and accounts for around half of all USH cases. USH2A patients show moderate to severe hearing loss from birth, with diagnosis of retinitis pigmentosa in the second decade of life and variable vestibular involvement. Although hearing aids or cochlear implants can provide some mitigation of hearing deficits, there are currently no treatments aimed at preventing or restoring vision loss in USH2A patients. In this review, we first provide an overview of the molecular biology of the USH2A gene and its protein isoforms, which include a transmembrane protein (TM usherin) and an extracellular protein (EC usherin). The role of these proteins in the inner ear and retina and their impact on the pathogenesis of USH2A is discussed. We review animal cell-derived and patient cell-derived models currently used in USH2A research and conclude with an overview of potential treatment strategies currently in preclinical development and clinical trials.

Anatomical and Functional Impacts of Congenital Bilateral Visual Deprivation on the Visual Pathway—A Comprehensive Review

“…There was a significant decrease in the intracranial volume and brain and cerebellum size, with a trend towards an increase in the size of the subarachnoid spaces. These data suggest that the process of the disease in Usher syndrome involves the entire brain and is not limited to the posterior fossa or auditory and visual systems [ 54 ]. Some recent fMRI results also indicate that early visual deprivation causes the reorganization of binaural spatial processing in the auditory cortex and that blind individuals may rely on alternative mechanisms for processing azimuth position [ 55 ].…”

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives

“…Usher syndrome (USH) is a disorder characterized by the loss of hearing and sight and represents about 50% of all hereditary deafness-blindness cases, with a prevalence from 4.4 to 16.6 per 100,000 people worldwide. Clinical manifestations comprise moderate to severe hearing loss from birth combined with vision impairment and gradual deterioration of rod photoreceptors-the RP hallmarks [96,97]. USH has complex characteristics because it can be subdivided into three types according to the genetic basis and corresponding clinical aspects.…”

“…The ush2a gene encodes two isoforms of usherins, essential proteins for cochlear hair cell development and the maintenance of photoreceptors [99]. Moreover, mutations in ush2a can also produce autosomal-recessive RP without hearing involvement [97].…”

Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

“…Mutations in the USH2A gene encoding usherin protein induce autosomal recessive non-syndromic RP and Usher syndrome [ 49 ]. The usherin has been known to house several motifs associated with extracellular matrix (ECM) proteins, such as laminin and fibronectin type III, which are essential for supporting the centrosome-cilium interface and the inner segment/outer segment region of photoreceptors [ 50 , 51 ]. The patient-specific ROs model carrying the USH2A mutation was established a decade ago [ 52 ].…”