Alternative titles; symbols
HGNC Approved Gene Symbol: USH1C
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38) : 11:17,493,900-17,544,416 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.1 | Deafness, autosomal recessive 18A | 602092 | Autosomal recessive | 3 |
| Usher syndrome, type 1C | 276904 | Autosomal recessive | 3 |
By serologic expression cloning, Scanlan et al. (1999) cloned USH1C, which they designated PDZ73, from a metastatic colon cancer cDNA expression library. The deduced full-length 652-amino acid protein has a calculated molecular mass of about 73 kD. It contains an N-terminal domain followed by 2 PDZ domains; a coiled-coil region with a bipartite nuclear localization signal; a PEST degradation sequence; a third PDZ domain; and a C-terminal domain. PDZ73 also has an N-glycosylation site and 17 putative phosphorylation sites. Scanlan et al. (1999) identified several splice variants. One variant encodes a deduced 403-amino acid protein with a calculated molecular mass of about 45 kD. This variant lacks the C-terminal half of the full-length protein, including the PEST sequence, the third PDZ domain, and the C-terminal region. Another variant, which predominates in brain, encodes a putative 328-amino acid protein with a calculated molecular mass of about 37 kD. This variant lacks the N-terminal half of the full-length protein and begins with part of the coiled-coil domain. Northern blot analysis revealed expression of a major 2.4-kb transcript in small intestine, colon, pancreas, kidney, and liver, with lower levels in testis. Although the 2.4-kb transcript was expressed in whole brain, a 1.3-kb transcript, which encodes the 37-kD protein, predominated. Northern blot analysis of specific brain regions detected expression of the 1.3-kb transcript specifically in spinal cord and medulla. RT-PCR detected expression of the transcript corresponding to the 73-kD protein in 13 of 20 samples tested. Expression of the transcript corresponding to the 45-kD protein was detected only in colon, small intestine, testis, brain, and kidney. Other variants showed more restricted expression. Immunohistochemical localization of PDZ73 revealed expression in epithelial cells, specifically at the apical cell border of the small intestine, in proximal and distal cortical tubules of the kidney, and in the cytoplasm of colonic epithelium. Scanlan et al. (1999) believed that the protein stained in these sections represents the 45-kD isoform.
Usher syndrome type I is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction, and blindness due to progressive retinitis pigmentosa. Usher syndrome type IC (USH1C; 276904) is a subtype mapping to 11p14.3 that had been described in a population of Louisiana Acadians and in a Lebanese family. By studying a subtracted mouse cDNA library derived from inner ear sensory areas, Verpy et al. (2000) demonstrated that the gene responsible for Usher syndrome type IC encodes a PDZ domain-containing protein. They named the protein encoded by the USH1C gene 'harmonin,' from the Greek word 'harmonia,' meaning 'assembling.' They showed that, in the mouse inner ear, only the sensory hair cells express harmonin. The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region. Several of these transcripts were absent from the eye.
Montell (2000) reviewed the information on the USH1C gene provided by the report of Verpy et al. (2000) and Bitner-Glindzicz et al. (2000). The organization of signaling and cytoskeletal proteins in complexes is coordinated by scaffold proteins composed of multiple protein interaction domains. One such module is the PDZ domain, so-called for the first 3 proteins known to contain it: PSD95 (602887), DLG (see 604090), and ZO1 (601009).
By genomic sequence analysis and FISH, Scanlan et al. (1999) mapped the PDZ73 gene to chromosome 11p15.4-p15.1.
Siemens et al. (2002) showed that harmonin and CDH23 (605516), another protein that is the site of mutations causing Usher syndrome, form a protein complex. Two PDZ domains in harmonin interact with 2 complementary binding surfaces in the CDH23 cytoplasmic domain. One of the binding surfaces is disrupted by sequences encoded by an alternatively spliced CDH23 exon that is expressed in the ear, but not in the retina. In the ear, CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the retina within the photoreceptor cell layer. Because Cdh23-deficient mice have splayed stereocilia, Siemens et al. (2002) suggested that CDH23 and harmonin are part of a transmembrane complex that connects stereocilia into a bundle, and that defects in the formation of this complex may disrupt stereocilia bundles and cause deafness in patients with Usher syndrome type I.
Boeda et al. (2002) noted that defects in the MYO7A (276903), CDH23, and harmonin genes result in forms of Usher syndrome. They observed severely disorganized hair bundles in shaker-1 mice, which carry a mutation in the Myo7a gene. Immunohistochemical analysis of differentiating hair cells indicated that Cdh23 was distributed normally, but harmonin b was not. Using human and mouse cDNA constructs and cells, they confirmed interaction between harmonin and CDH23 in vitro and in vivo. They also provided evidence that harmonin b anchors CDH23 to the stereocilia microfilaments and interacts directly with MYO7A, which conveys harmonin b along the actin core of the developing stereocilia. Boeda et al. (2002) proposed that the shaping of the hair bundle relies on a functional unit composed of MYO7A, harmonin b, and CDH23, and that the interaction of these proteins ensures the cohesion of the stereocilia.
By using cotransfection and immunolocalization techniques, Adato et al. (2005) documented the interaction between SANS (USH1G; 607696) and harmonin, and also determined that SANS binds to myosin VIIa. The authors noted that harmonin b could interact with all harmonin isoforms and that harmonin bound to protocadherin-15 (PCDH15; 605514). Adato et al. (2005) proposed that, via its binding to myosin VIIa and/or harmonin, SANS controls the hair bundle cohesion and proper development by regulating the traffic of USH1 proteins en route to the stereocilia.
Reiners et al. (2005) demonstrated a molecular interaction between the scaffold protein harmonin, the USH2A protein usherin (608400), VLGR1 (USH2C; 602851), and NBC3 (SLC4A7; 603353). The authors pinpointed these interactions to the PDZ1 domain of harmonin and the PDZ-binding motifs at the C termini of the USH2 proteins and NBC3. USH2A, VLGR1, and NBC3 are coexpressed with the USH1 protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. The authors concluded that the USH2 proteins and NBC3 are partners in the supramolecular USH protein network in the retina and inner ear.
Bahloul et al. (2010) found that both isoforms of mouse Cdh23 bound directly to the harmonin A isoform and to the tail of myosin-7a. The 3 proteins formed a complex that interacted with phosphatidylinositol 4,5-bisphosphate in synthetic liposomes. Knockout of Cdh23 in mice resulted in loss of harmonin from the apex of hair bundles in the organ of Corti and caused redistribution of a weakened myosin-7a signal along stereocilia.
In patients with Usher syndrome type IC, Verpy et al. (2000) found a splice site mutation (605242.0001), a frameshift mutation (605242.0002), and the expansion of an intronic variable number of tandem repeats (VNTRs) (605242.0003) in the USH1C gene. Verpy et al. (2000) proposed that mutation in the USH1C gene also underlies the form of nonsyndromic autosomal recessive neurosensory deafness designated DFNB18 (DFNB18A; 602092), which maps to the same region of 11p. Ouyang et al. (2002) indeed found a family with profound deafness without retinitis pigmentosa due to a mutation in the USH1C gene (605242.0009). Ahmed et al. (2002) identified a splice site mutation in intron 12 of the harmonin gene (605242.0008) in a family with DFNB18A.
Bitner-Glindzicz et al. (2000) identified a partial deletion of the USH1C gene in a contiguous gene deletion syndrome (606528).
Ouyang et al. (2003) determined the frequency of USH1C mutations as a cause of Usher syndrome type I by studying 128 probands, 7 from Acadian and 121 from non-Acadian populations. All 7 Acadian Usher syndrome type I patients were found to be homozygous for both the 216G-A mutation (605242.0004) and the 9-repeat VNTR (605242.0003), which the authors referred to as the Acadian alleles, confirming previous evidence for a founder effect by haplotype analysis. However, USH1C mutations were identified in only 2 of the non-Acadian probands (1.65%): 1 from Pakistan who was homozygous for a 1-bp insertion (238_239insC; 605242.0002) and 1 from Canada who was homozygous for the Acadian alleles. The affected haplotypes in the Canadian patient in comparison with the Acadian patients yielded evidence for a founder effect. Ouyang et al. (2003) suggested that Usher syndrome type IC is a relatively rare form of Usher syndrome type I in non-Acadian populations, and that the high frequency of the 238_239insC mutation in the study of Zwaenepoel et al. (2001) in Germany may reflect a founder effect.
In the U.K., Blaydon et al. (2003) found no mutations in the USH1C gene in patients with nonsyndromic deafness but found more instances of USH1C mutations in Usher syndrome type I than had previously been thought to occur. The 238_239insC mutation (605242.0002) was found in homozygous state in an Usher syndrome type I patient of Greek Cypriot origin.
In a metaanalysis of gross insertions causing human genetic disease based on sequence data in the Human Gene Mutation Database, Chen et al. (2005) found an example of a 36-bp insertion in exon 9 of the USH1C gene, the origin of which was the mitochondrial chromosome. Turner et al. (2003) reported a 72-bp insertion of mitochondrial DNA in the GLI3 gene (165240).
In 2 sibs from a Caucasian British family with hearing loss diagnosed at 4 years of age and retinitis pigmentosa of the 'sector' type, who were negative for pathogenic changes in 7 other Usher-associated genes, Saihan et al. (2011) identified compound heterozygosity for a missense mutation (R103H; 605242.0011) and a splice site mutation (605242.0012) in the USH1C gene.
In 12 patients from 8 Israeli families of Yemenite Jewish origin with retinitis pigmentosa and late-onset hearing loss, Khateb et al. (2012) identified homozygosity for a 1-bp deletion in the USH1C gene (1220delG; 605242.0013). A carrier frequency of 0.008 for the 1220G mutation was found in the Israeli Yemenite Jewish population.
Johnson et al. (2003) mapped 2 recessive, allelic murine mutations causing circling behavior and deafness to the same region on chromosome 7. The 'deaf circler' (dfcr) mutation is a 12.8-kb intragenic deletion in Ush1c that eliminates 3 constitutive and 5 alternatively spliced exons. The 'deaf circler-2 Jackson' (dfcr-2J) mutation is a 1-bp deletion in an alternatively spliced exon of Ush1c that creates a transcriptional frameshift, changing 38 amino acid codons before introducing a premature stop codon. Both mutations cause congenital deafness and severe balance deficits due to inner ear dysfunction. The stereocilia of cochlear hair cells are disorganized and splayed in mutant mice, with subsequent degeneration of the hair cells and spiral ganglion cells. Harmonin had been shown to bind, by means of its PDZ-domains, with the products of other Usher syndrome genes, including Myo7a, Cdh23, and Sans. The complexes formed by these protein interactions are thought to be essential for maintaining the integrity of hair cell stereocilia.
In patients with Usher syndrome type IC (276904) in a consanguineous Lebanese family (Saouda et al., 1998), Verpy et al. (2000) identified deletion of 1 nucleotide at the intron 5/exon 6 junction of the USH1C gene. This mutation (IVS5-2delA) affected the invariant A of the acceptor splice site AG dinucleotide and was therefore expected to lead to aberrant splicing, such as a skipping of the 25-bp exon 6, creating a premature stop codon in exon 8. The same mutation was found in homozygous state in 8 Usher syndrome type I affected children from an unrelated Lebanese family.
In a consanguineous Muslim family living in England with Usher syndrome type IC (276904) with 3 affected children, Verpy et al. (2000) found insertion of a C within a stretch of 6 consecutive cytosines (nucleotide positions 233-238) in exon 3 of the USH1C gene. This insertion (238_239insC) was expected to result in translation of 68 out-of-frame amino acids and protein termination at codon 148 in exon 5. Verpy et al. (2000) found the same 238_239insC mutation in 4 patients from Germany (all of European descent) with Usher syndrome but no detected mutations of MYO7A (276903). Bitner-Glindzicz et al. (2000) likewise found this insertion in a Pakistani family.
Zwaenepoel et al. (2001) found that all carriers of the 238_239insC mutation share a common haplotype. A different common haplotype was found in 2 carriers of the IVS1+1G-T mutation (605242.0005). Zwaenepoel et al. (2001) proposed a founder effect of these 2 mutations.
In Louisiana-Acadian patients with Usher syndrome type IC (276904), Verpy et al. (2000) found no mutation in the coding sequence of the harmonin gene; however, they detected an expansion of a variable number of tandem repeats (VNTR) of a 45-bp element in intron 5 of the USH1C gene. They detected no control individuals with 2 alleles bearing more than 6 repeats. In all but 1 of 11 Acadian patients, they found an allele with 9 tandem repeats in the homozygous state. These 10 individuals were from 7 families. The remaining Acadian patient carried the 9 tandem repeats on 1 chromosome and the 238_239insC mutation (605242.0002) on the other. Verpy et al. (2000) proposed that this 405-bp intronic sequence composed of 9 tandem repeats was responsible for the disease in the Acadian population of Louisiana. The repeat expansion was predicted to inhibit transcription, as shown for the expanded GAA triplet repeats from intron 1 of the Friedreich ataxia gene (229300). Alternatively, it may cause abnormal posttranscriptional processing.
Savas et al. (2002) found that 43 of 44 Acadian patients with Usher syndrome were homozygous for both a 216G-A mutation (605242.0004) and the 45-bp VNTR polymorphism in the USH1C gene. The remaining Acadian patient was a compound heterozygote for the 216G-A allele (with the intron 5 VNTR in cis) and 238_239insC (605242.0002), an USH1C mutation found in other populations. The findings demonstrated that the VNTR polymorphism, designated 9VNTR(t,t), had complete linkage disequilibrium with the 216G-A mutation in the Acadian population.
In cell lines from an Acadian family with Usher syndrome type IC (276904), Bitner-Glindzicz et al. (2000) found a G-to-A change at position 216 of the USH1C cDNA. The affected individual was homozygous for the substitution and the parents were heterozygous. Although this substitution did not change an amino acid, examination of the sequence suggested that it might create a new splice site. Analysis of USH1C lymphoblastoid cDNA from the Acadian family showed that the affected individual produced a shortened RT-PCR product. Sequencing revealed a 39-bp deletion, consistent with the creation of a new splice site within exon 3.
Savas et al. (2002) found that 43 of 44 Acadian patients with Usher syndrome were homozygous for both the 216G-A mutation and for the 45-bp VNTR polymorphism in intron 5 (605242.0003) of the USH1C gene. The remaining Acadian patient was a compound heterozygote for the 216G-A allele (with the intron 5 VNTR in cis) and 238_239insC (605242.0002), an USH1C mutation found in other populations. The findings demonstrated that the VNTR polymorphism, designated 9VNTR(t,t), had complete linkage disequilibrium with the 216G-A mutation in the Acadian population. Among 82 Acadian controls, 1 was heterozygous for 216G-A/9VNTR(t,t). The 238_239insC mutation was not found in Acadian controls.
A complete USH1C mutation screen in 4 carriers of the 238_239insC mutation (605242.0002) resulted in the detection of the second mutation in all of the carriers, and the identification of 3 novel mutations of which 2 were splice site mutations (IVS1+1G-T; IVS5+1G-A, 605242.0006) and the other a nonsense mutation (R31X; 605242.0007) (Zwaenepoel et al., 2001).
Zwaenepoel et al. (2001) found that 2 carriers of the IVS1+1G-T mutation share a common haplotype. A different common haplotype was found in all carriers of the 238_239insC mutation. Zwaenepoel et al. (2001) proposed a founder effect of these 2 mutations.
A complete USH1C mutation screen in 4 carriers of the 238_239insC mutation (605242.0002) resulted in the detection of the second mutation in all of the carriers, and the identification of 3 novel mutations of which 2 were splice site mutations (IVS5+1G-A; and IVS1+1G-T, 605242.0005) and the other a nonsense mutation (R31X; 605242.0007) (Zwaenepoel et al., 2001).
In an extensive genetic study of 9 Usher syndrome genes in 172 patients with Usher syndrome due to various genetic defects, Le Quesne Stabej et al. (2012) found that mutations in the USH1C gene were the second most common defect, accounting for 14.9% of families. Four families carried the intron 5 splice site mutation (495+1G-A), and haplotype analysis indicated a founder effect.
A complete USH1C mutation screen in 4 carriers of the 238_239insC mutation (605242.0002) resulted in the detection of the second mutation in all of the carriers, and the identification of 3 novel mutations: arg31-to-arg (R31X) and 2 splice site mutations (IVS5+1G-A, 605242.0006; and IVS1+1G-T, 605242.0005) (Zwaenepoel et al., 2001).
In an Indian family in which nonsyndromic recessive deafness (DFNB18A; 602092) had been mapped to the same region of 11p as USH1C, Ahmed et al. (2002) identified a leaky splice site mutation in the harmonin gene, a G-to-C transversion at the +5 position of intron 12. Although affected individuals were homozygous for the mutation, wildtype spliced mRNA having exons 11 and 12 as well as mRNA that skipped exon 12 were found.
In 1 of 32 Chinese multiplex families with nonsyndromic recessive deafness without retinitis pigmentosa (DFNB18A; 602092), Ouyang et al. (2002) found a C-to-G transversion in the alternatively spliced exon D of the USH1C gene, predicting an arg608-to-pro (R608P) substitution in the proline-, serine-, and threonine-rich region of harmonin.
This variant, formerly titled USHER SYNDROME, TYPE IC, has been reclassified based on the findings of Shearer et al. (2014).
In a U.K. patient with type I Usher syndrome (USH1C; 276904), Blaydon et al. (2003) identified a 388G-A transition in exon 5 of the USH1C gene, resulting in a val130-to-ile (V130I) mutation in the first PDZ domain of the protein. No mutation was identified on the other allele.
Based on allele frequency in 8,595 controls from 12 populations (maximum minor allele frequency = 0.0600), Shearer et al. (2014) recategorized the V130I variant in the USH1C gene as benign.
In a 42-year-old woman and her 40-year-old brother from a Caucasian British family with hearing loss diagnosed at 4 years of age and retinitis pigmentosa of the 'sector' type (USH1C; 276904), Saihan et al. (2011) identified compound heterozygosity for mutations in the USH1C gene: a 308G-A transition, resulting in an arg103-to-his (R103H) substitution, and a splice site mutation (IVS16-1G-T; 2227-1G-T; 605242.0012) predicted to abolish the invariant AG dinucleotide splice acceptor site and create a new acceptor site 10 nucleotides downstream that would result in skipping of exon 22 and an in-frame loss of 18 amino acids. The sibs' unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 866 control chromosomes. Saihan et al. (2011) noted that the R103H mutation had previously been reported: it was identified in compound heterozygosity with a different splice site mutation in a French USH1 patient, and was not found in a panel of 352 chromosomes in that study (Roux et al., 2006).
For discussion of the splice site mutation (IVS16-1G-T) in the USH1C gene that was found in compound heterozygous state in a 42-year-old woman and her 40-year-old brother with Usher syndrome type IC (USH1C; 276904) by Saihan et al. (2011), see 605242.0011.
In 12 patients from 8 Israeli families of Yemenite Jewish origin with retinitis pigmentosa and late-onset hearing loss (USH1C; 276904), Khateb et al. (2012) identified homozygosity for a 1-bp deletion (1220delG) in alternative exon 15 of the USH1C gene, predicted to cause a frameshift (Gly407GlufsTer56). Extensive RT-PCR analysis revealed that the novel splice variant includes all USH1C coding exons and is ubiquitously expressed at relatively low levels.
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