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.
Highlights
Usher syndrome (USH) is the most common cause of genetic deafblindness and follows an autosomal recessive inheritance
MYO7A, USH1C, CDH23, PCDH15, USH1G and CIB2 cause USH type 1 (USH1); USH2A, ADGRV1 and WHRN are accountable for USH type 2 (USH2); and CLRN1 is the only gene associated with USH type 3 (USH3) far
In 2015, Lenassi et al established an allele hierarchy of USH2A variants in 457 patients from three different cohorts [15], to identify the mutations that resulted in either retinitis pigmentosa (RP) or USH. Their results showed that, null alleles were responsible for the syndromic form, missense variants were associated with RP in a higher proportion compared to USH, and the phenotype depended on the second causal variant
Summary
Usher syndrome (USH) is the most common cause of genetic deafblindness and follows an autosomal recessive inheritance. This disorder is characterized by the combination of a degenerative vision loss condition known as retinitis pigmentosa (RP), sensorineural hearing loss (SNHL) and, sometimes, vestibular dysfunction. Even though a recent report has cast doubts about the vestibular phenotypic differences among the USH subtypes [2], this disease is traditionally classified into three different subtypes depending on the age of onset, severity and progression of the symptoms, and the presence or absence of vestibular dysfunction [3]. USH type 3 (USH3) is the rarest form and is characterized by postlingual progressive SNHL, and both a variable onset age of RP and vestibular function.
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