Usher syndrome: clinical features, molecular genetics and advancing therapeutics

Abstract

Usher syndrome has three subtypes, each being clinically and genetically heterogeneous characterised by sensorineural hearing loss and retinitis pigmentosa (RP), with or without vestibular dysfunction. It is the most common cause of deaf–blindness worldwide with a prevalence of between 4 and 17 in 100 000. To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome. Variants in these genes can also cause non-syndromic RP and deafness. Genotype–phenotype correlations have been described for several of the Usher genes. Hearing loss is managed with hearing aids and cochlear implants, which has made a significant improvement in quality of life for patients. While there is currently no available approved treatment for the RP, various therapeutic strategies are in development or in clinical trials for Usher syndrome, including gene replacement, gene editing, antisense oligonucleotides and small molecule drugs.

Early Disruption of Photoreceptor Cell Architecture and Loss of Vision in a Humanized Pig Model of Usher Syndrome

“…Usher syndrome (USH) is the most common form of inherited deaf-blindness in humans ( 1 ). USH is clinically and genetically heterogeneous, with at least 12 genes assigned to three clinical USH types ( 2, 3 ). The most severe of them is USH1, characterized by profound hearing loss from birth on, vestibular areflexia, and pre-pubertal onset of Retinitis pigmentosa (RP).…”

Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

“…Those models allowed researchers to notice a common phenotype of abnormal hair bundle shape characteristic of sensory cells ( Lefevre et al, 2008 ; Mburu et al, 2003 ; McGee et al, 2006 ; Michel et al, 2017 ). Extensive reviews regarding the genetics and mechanisms of Usher syndrome are available ( El-Amraoui & Petit, 2014 ; French et al, 2020 ; Geleoc & El-Amraoui, 2020 ; Toms, Pagarkar, & Moosajee, 2020 ).…”

Potential therapy for progressive vision loss due to PCDH15-associated Usher Syndrome developed in an orthologous Usher mouse

“…Night blindness is an early sign in USH1 subjects followed by constriction of the visual field (tunnel vision) and finally clinical blindness (Vernon, 1969). Characteristic fundus features include pigmentary retinopathy, narrowing of the retinal vessels, and a pale appearance of the optic disk (Toms, Pagarkar et al, 2020). Vestibular dysfunction in USH1 manifests as a delay in development of independent ambulation while hearing loss is usually severe to profound, congenital and sensorineural (Ahmed, Riazuddin et al, 2003b, Smith, Berlin et al, 1994.…”