![]() (2005, 2012) demonstrated that compound heterozygous Cdh23/ Pcdh15 Myo7a/ Ush1g Myo7a/ Cdh23 Myo7a/ Pcdh15 mice exhibited HL and disorganized hair-cell stereocilia. However, several studies have shown the digenic inheritance of deafness caused by mutations in USH genes and USH modifier PDZD7 in mice and humans ( Zheng et al., 2005, 2012 Ebermann et al., 2011 Bonnet et al., 2016). USH has been considered to be a monogenic, genetically heterogeneous disease from the very beginning. Usher syndrome is genetically heterogeneous with nine causative genes confirmed, two suspected, and a further three candidate loci having been mapped. USH was later named after Charles Usher, a Scottish ophthalmologist who established its heritability in 1914 based on 69 cases ( Usher, 1914). The syndrome was first described in 1858, by German ophthalmologist Albrecht Von Graefe, in three siblings with simultaneous congenital deafness and RP ( von Graefe, 1858 Boughman et al., 1983). USH has an estimated global prevalence of between 4 and 17 cases per 100,000 individuals, and accounts for approximately 50% of all hereditary deaf-blindness cases and 3–6% of all childhood hearing loss (HL) cases ( Boughman et al., 1983 Fortnum et al., 2001 Kimberling et al., 2010 Lenarduzzi et al., 2015). Usher syndrome (USH) is an autosomal recessive (AR) disorder characterized by sensorineural hearing loss (SNHL), vision loss due to retinitis pigmentosa (RP), and vestibular dysfunction ( Geleoc and Holt, 2014 Mathur and Yang, 2015). 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. 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. 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. These signals are then detected by the auditory nerve fibers, transmitted to the brain and interpreted as sound. 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. 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. There are currently nine confirmed and two suspected USH-causative genes, and a further three candidate loci have been mapped. 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. Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance. 6School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia. ![]()
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