Usher Syndrome: Genetics of a Human Ciliopathy

Abstract

Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to be causative of USH, and six more related to the disease. These genes encode proteins of a diverse nature, which interact and form a dynamic protein network called the “Usher interactome”. In the organ of Corti, the USH proteins are essential for the correct development and maintenance of the structure and cohesion of the stereocilia. In the retina, the USH protein network is principally located in the periciliary region of the photoreceptors, and plays an important role in the maintenance of the periciliary structure and the trafficking of molecules between the inner and the outer segments of photoreceptors. Even though some genes are clearly involved in the syndrome, others are controversial. Moreover, expression of some USH genes has been detected in other tissues, which could explain their involvement in additional mild comorbidities. In this paper, we review the genetics of Usher syndrome and the spectrum of mutations in USH genes. The aim is to identify possible mutation associations with the disease and provide an updated genotype–phenotype correlation.

Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes

“…The specific relevance of harmonin_b variants for hearing is also illustrated by mutations in the CC2 or the PST domain, causing autosomal recessive deafness (DFNB18A) rather than USH in human patients (Ouyang et al , 2002 ) or in a naturally occurring deaf‐circler mouse line (Johnson et al , 2003 ). In contrast, USH‐causing mutations are located in the common N‐harm, PDZ, or CC1 domains (Fuster‐Garcia et al , 2021 ).…”

Expression and subcellular localization of USH1C/harmonin in the human retina provide insights into pathomechanisms and therapy

“…USH is considered a retinal ciliopathy because of defects in photoreceptor cilia and other primary cilia (Bujakowska et al, 2017;May-Simera et al, 2017;Samanta et al, 2019). Among the three clinical subtypes of USH (USH1, USH2, and USH3) USH1 is the most severe, characterized by profound congenital hearing impairment or deafness, vestibular dysfunction, and early onset of progressive photoreceptor degeneration (Fuster-Garcia et al, 2021).…”

Usher Syndrome

“…USH can be considered a ciliopathy [ 20 , 21 ] because it affects specific genes and proteins involved in various ciliary cell functions. Most genetic mutations cause the destruction and disruption of different structural proteins that play important roles in auditory, visual, and vestibular functions.…”