Genetics and pathological mechanisms of Usher syndrome

Abstract

Usher syndrome (USH) comprises a group of autosomal recessively inherited disorders characterized by a dual sensory impairment of the audiovestibular and visual systems. Three major clinical subtypes (USH type I, USH type II and USH type III) are distinguished on the basis of the severity of the hearing loss, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). Since the cloning of the first USH gene (MYO7A) in 1995, there have been remarkable advances in elucidating the genetic basis for this disorder, as evidence for 11 distinct loci have been obtained and genes for 9 of them have been identified. The USH genes encode proteins of different classes and families, including motor proteins, scaffold proteins, cell adhesion molecules and transmembrane receptor proteins. Extensive information has emerged from mouse models and molecular studies regarding pathogenesis of this disorder and the wide phenotypic variation in both audiovestibular and/or visual function. A unifying hypothesis is that the USH proteins are integrated into a protein network that regulates hair bundle morphogenesis in the inner ear. This review addresses genetics and pathological mechanisms of USH. Understanding the molecular basis of phenotypic variation and pathogenesis of USH is important toward discovery of new molecular targets for diagnosis, prevention and treatment of this debilitating disorder.

Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6

“…1 Each of these syndromes is caused by mutations in more than one gene. 1,2 Syndromic hearing loss can also occur in a number of mitochondrial diseases. 3 Similarly, nonsyndromic hearing loss comprises autosomal dominant (DNFA), autosomal recessive (DFNB) and X-linked (DFNX or DFN) subtypes, as well as some mitochondrial forms (Hereditary Hearing Loss Homepage, http://hereditaryhearingloss.org/).…”

Usher proteins in inner ear structure and function

“…Clinically, USH is classified into three presenting subtypes, type I, II, and III based on the severity and age of onset (2). USH type I (USH1) is the most genetically heterogeneous: 14 loci have been mapped for USH, and genes for 11 have been identified (19,27,40). Although mutations in each of these genes cause USH, certain missense mutations cause only deafness or only retinitis pigmentosa (2,27,38,40).…”

Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction

“…MYO7A, sans, harmonin, and CDH23 are all implicated in Usher type I (USH1) syndrome (16), characterized by deafness, vestibular dysfunction, and retinopathy leading to blindness. The localization reported for sans in hair cells are at the basal body (17) and more recently at the stereocilia tips (18).…”