Disease relevance of Usher Syndromes

• The USH2A gene is mutated in patients with Usher syndrome type IIa, which is the most common subtype of Usher syndrome and is characterized by hearing loss and retinitis pigmentosa [1].
• The Usher syndromes (USH) are a group of autosomal recessive diseases characterized by progressive pigmentary retinopathy and sensorineural hearing loss [2].
• The colocalization of hCHML and Usher syndrome type II, as well as the clinical similarities between choroideremia and Usher syndrome type II, make hCHML a candidate gene for this disorder [3].
• PURPOSE: To investigate the retinal disease expression in USH2C, the subtype of Usher syndrome type 2 recently shown to be caused by mutation in the VLGR1 gene, and compare results with those from USH2A, a more common cause of Usher syndrome [4].
• Defects in myosin-VIIa cause the shaker-1 phenotype in mice and Usher syndrome 1B in human, which are characterized by deafness, lack of vestibular function, and (in human) progressive retinal degeneration [5].

High impact information on Usher Syndromes

• Mice lacking NBC3 develop blindness and auditory impairment because of degeneration of sensory receptors in the eye and inner ear as in Usher syndrome [6].
• Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D [7].
• Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D [8].
• Mutations in human CDH23 cause Usher syndrome type 1D and thus, establish waltzer as the mouse model for USH1D [7].
• Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa (RP) [8].

Chemical compound and disease context of Usher Syndromes

• The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions [9].
• Identification of a rat model for usher syndrome type 1B by N-ethyl-N-nitrosourea mutagenesis-driven forward genetics [10].
• Macular pigment and lutein supplementation in retinitis pigmentosa and Usher syndrome [11].
• A heterozygous sequence variant changing a glycine to arginine at codon 178 was found in one Usher syndrome type II (USH2) patient, while the other USH2 patients did not show any coding sequence variant [12].

Biological context of Usher Syndromes

• We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10) [8].
• CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness [13].
• Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II [1].
• Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein [14].
• Sensorineural deafness and retinitis pigmentosa (RP) are the hallmarks of Usher syndrome (USH) but are also prominent features in peroxisomal biogenesis defects (PBDs); both are autosomal recessively inherited [15].

Anatomical context of Usher Syndromes

• Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B [16].
• They demonstrate that a myosin may function in a cilium and suggest that abnormal opsin transport might contribute to blindness in Usher syndrome [17].
• Limited sequence homology to stargazin, a cerebellar synapse four-transmembrane-domain protein, suggests a role for clarin-1 in hair cell and photoreceptor cell synapses, as well as a common pathophysiological pathway for different Usher syndromes [18].
• The deaf-circling Ames waltzer (av) mouse harbors a mutation in the protocadherin 15 (Pcdh15) gene and is a model for inner ear defects associated with Usher syndrome type 1F [19].
• The left temporal bone of patient 2, classified as Usher syndrome genetic subtype USH1D or USH1F, demonstrated the typical signs of severe cochleosaccular degeneration [20].

Gene context of Usher Syndromes

• Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II [21].
• Both were shown to be mutations of the Ush1c gene, the mouse ortholog of the gene responsible for human Usher syndrome type IC and for the non-syndromic deafness disorder DFNB18 [22].
• Myosin VIIa functions in the outer retina, and loss of this function causes human blindness in Usher syndrome type 1B (USH1B) [23].
• The linkage interval contains the Usher syndrome 1G gene (USH1G) that is mutated in patients with Usher syndrome (USH) type 1g and encodes the SANS protein [24].
• MYO7A mutations are responsible for Usher syndrome type Ib, the most common genetic subtype of Usher I [25].

Analytical, diagnostic and therapeutic context of Usher Syndromes

• Molecular cloning and domain structure of human myosin-VIIa, the gene product defective in Usher syndrome 1B [5].
• Denaturing high-performance liquid chromatography (DHPLC) was used to screen 14 UK patients with Usher syndrome type 1, in order to assess the contribution of mutations in USH1C to type 1 Usher [26].
• Audiometric features, evaluated by serial pure tone audiometry and speech recognition tests (n = 31), were analysed in 59 Finnish Usher syndrome type III patients (USH3) with Finmajor/Finmajor (n = 55) and Finmajor/Finminor (n = 4) USH3A mutations [27].

References