Disease relevance of USH1C

• The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C [1].
• Usher syndrome 1C (USH1C) is a congenital condition manifesting profound hearing loss, the absence of vestibular function, and eventual retinal degeneration [2].
• To clarify the functional role in colon cancer cells, we transfected AIE-75 gene into SW480 colon cancer cells which do not express AIE-75 [3].
• Expression of AIE-75 PDZ-domain protein induces G2/M cell cycle arrest in human colorectal adenocarcinoma SW480 cells [3].
• Construction of a YAC contig encompassing the Usher syndrome type 1C and familial hyperinsulinism loci on chromosome 11p14-15.1 [4].

High impact information on USH1C

• A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C [5].
• The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C [1].
• The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18 [1].
• The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region [5].
• We identified this gene (USH1C), encoding a PDZ-domain-containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas [5].

Chemical compound and disease context of USH1C

• Usher syndrome type IC is a rare, autosomal recessive sensorineural disorder caused by mutations in the USH1C gene, which encodes a PDZ-domain protein named harmonin [6].

Biological context of USH1C

• In another family, haplotype segregation was consistent with linkage to USH1C [7].
• We performed mutation screening by single strand conformation polymorphism (SSCP) analysis and direct sequencing on 33 USH1 patients previously excluded for USH1B and USH1C [8].
• In these protein-protein complexes harmonin acts as the scaffold protein binding these USH1 molecules via its PDZ domains [9].
• None carried any mutations in these exons of USH1C [10].
• In addition, a 45-bp variable number of tandem repeat (VNTR) polymorphism was found in intron 5 of USH1C [11].

Anatomical context of USH1C

• Colocalization of Pcdh15 with harmonin was found at the base of the photoreceptor outer segment, where newly synthesized disk membranes are present [9].
• Our findings show that USH1C mutations can also cause non-syndromic deafness and that some harmonin isoforms are specifically required for inner ear function [10].
• Analysis of all the markers in the USH1C region flanked by D11S1397 and D11S1888 on the J1 somatic cell hybrid panel localized USH1C to the upper half of chromosome 11p14 [12].
• AIE-75 was predominantly distributed in the epithelial cells of the luminal surface and the upper half of the crypts of the intestine and in the proximal renal tubulus [13].
• Three of the 48 antigens showed a differential pattern of mRNA expression, with NY-CO-27 (galectin-4) expressed primarily in gastrointestinal tract, and NY-CO-37 and -38 showing a pattern of tissue-specific isoforms [14].

Associations of USH1C with chemical compounds

• We and others recently reported that the scaffold protein harmonin (USH1C-gene product) integrates all identified USH1 molecules in a USH1-protein network [15].
• In one family, congenital profound deafness without RP was associated with a C to G transversion in the alternatively spliced exon D, predicting an arginine to proline substitution at codon 608 in the proline-, serine- and threonine-rich region of harmonin [10].
• Screening of proteins that bound to PDZ domains of AIE-75 by a yeast two hybrid system showed that three serine/threonine phosphatase catalytic subunits (PP2AC-alpha, PP2AC-beta, and PPP6C) could bind to AIE-75 [3].
• We have cloned a human cDNA, DELGEF (deafness locus associated putative guanine nucleotide exchange factor), derived from a 225 kb genomic sequence of chromosome 11p14, critical for the Usher 1C syndrome and for DFNB18, a locus for non-syndromic sensorineural deafness [16].
• Otog, the gene encoding otogelin, a glycoprotein specific to all the acellular membranes of the inner ear, is also localized to mouse Chr 7, but in a region more proximal to the twister mutation, homologous to the short arm of human Chr 11 (11p15) carrying the two deafness loci, DFNB 18 and USH C [17].

Physical interactions of USH1C

• MCC2 protein binds the first PDZ domain of AIE-75 with its C-terminal amino acids -DTFL [18].

Other interactions of USH1C

• A previous screening of 18 unrelated USH1 patients, without a detected MYO7A mutation, for the three USH1C mutations described to date had demonstrated the presence of the 238-239insC mutation in the heterozygous state in four of them [19].
• Recently, the USH1C gene was shown to encode harmonin, a PDZ domain-containing protein [19].
• By molecular modeling, we provide evidence that this mutation impairs the interaction of SANS with harmonin [20].
• Since the MCC1 does not bind to AIE-75 and the MCC2 displays different expression patterns in various organs compared to MCC1, they appear to play distinct roles in cells [18].
• PURPOSE: To search for patients with Usher syndrome type IC among those with Usher syndrome type I who reside in New England. METHODS: Genotype analysis of microsatellite markers closely linked to the USH1C locus was done using the polymerase chain reaction [21].

Analytical, diagnostic and therapeutic context of USH1C

• 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 [22].
• Harp is expressed in many of the same epithelia as harmonin and co-localization of native harp and harmonin was demonstrated by confocal microscopy in pancreatic duct epithelium and in a pancreatic beta-cell line [23].
• Using a yeast two-hybrid assay, we show that the first PDZ domain of harmonin interacts with a novel protein, designated harp for harmonin-interacting, ankyrin repeat-containing protein [23].

References