DiagnosisClinical DiagnosisA diagnosis of Usher syndrome type I requires the following:Congenital (i.e., prelingual) profound bilateral sensorineural hearing loss (see Deafness and Hereditary Hearing Loss Overview)No significant vestibular responsesRetinitis pigmentosa (RP)Normal general health and intellect; otherwise normal physical examinationA family history consistent with autosomal recessive inheritanceMolecular Genetic TestingGenes. Five genes associated with Usher syndrome type I have been identified. Subtypes of Usher syndrome type I and associated genes:USH1B: MYO7AUSH1C: USH1CUSH1D: CDH23USH1F: PCDH15USH1G: USH1GOther lociA sixth locus associated with Usher syndrome type I (USH1E) has been mapped to 21q21; the gene is not yet known. A seventh locus associated with Usher syndrome type I (USH1H) has been mapped to 15q22-q23 [Ahmed et al 2009]. USH1A. Gerber et al [2006] provide evidence that the USH1A locus does not exist; six of the nine families from the Bressuire region of France originally reported to map to this locus have been found to have mutations in MYO7A (USH1B).TestingSequence analysis of the coding region and flanking exonic regions (see Table 1) Targeted mutation analysis PCDH15 (USH1F). Testing for the mutation p.Arg245X in exon 8MYO7A (USH1B). A genotyping microarray based on the array primer extension (APEX) method that screens for selected known mutations in MYO7A [Cremers et al 2007]Deletion/duplication analysisMYO7A (USH1B). Rare deletion of exon(s) has been reported (see Table A. Genes and Databases, Locus Specific).USH1C (USH1C). Rare deletion of exon(s) has been reported [Bitner-Glindzicz et al 2000].CDH23 (USH1D). No deletions or duplications involving CDH23 as causative of Usher Syndrome 1D have been reported. PCDH15 (USH1F). Rare deletion of exon(s) has been reported [Roux et al 2006].Linkage analysis Table 1. Summary of Molecular Genetic Testing Used in Usher Syndrome Type I (USH1)View in own windowPercent of All USH1 ^{1Gene Symbol
(Locus Name)Test MethodMutations DetectedMutation Detection Frequency by Gene and Test Method 2Test Availability 39%-55%MYO7A
(USH1B)Sequence analysisSequence variants 3 ~90% 1, 4ClinicalTargeted mutation analysisPanel of targeted known sequence variants 5See footnote 5Deletion / duplication analysis 6Exonic or whole-gene deletionsUnknown6%-7% 7USH1C
(USH1C)Sequence analysisSequence variants 3UnknownClinicalDeletion / duplication analysis 6Exonic or whole-gene deletions19%-35%CDH23
(USH1D)Sequence analysisSequence variants 3~90% 1ClinicalDeletion / duplication analysis 6, 8Exonic or whole-gene deletionsUnknownRareUnknown
(USH1E)Linkage analysisN/AN/AResearch only 11%-19%PCDH15
(USH1F)Sequence analysisSequence variants 3UnknownClinicalTargeted mutation analysisp.Arg245XSee footnote 9Deletion / duplication analysis 6Exonic or whole-gene deletionsUnknownRare (7%)USH1G
(USH1G)Sequence analysisSequence variants 3UnknownClinicalRareUnknown
(USH1H)Linkage analysisN/AN/AResearch only N/A = not applicable1. Ouyang et al [2005], Roux et al [2006]2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Maubaret et al [2005], Jaijo et al [2007]5. Mutations in testing panels and mutation detection frequency may vary by laboratory.6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.7. Almost all Usher syndrome type I in the Acadian population is USH1C.8. No deletions or duplications involving CDH23 as causative of Usher syndrome 1D have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)9. The p.Arg245X mutation is detected in a large percentage of Ashkenazi Jewish individuals with USH1F. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming/establishing the diagnosis in a proband If the individual is of Acadian or Ashkenazi Jewish ancestry, molecular genetic testing begins with testing for specific mutations in the USH1C and PCDH15 genes, respectively (see Table 1, footnotes 7 and 9). If the individual does not have these ancestries or mutations are not found in these two genes, sequencing of MYO7A, CDH23, PCDH15, USH1C, and USH1G is performed in that order, followed by deletion/duplication analyses.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersMY07AUsher syndrome type III. Compound heterozygosity for the mutations p.Leu651Pro and p.Arg1602Gln in MYO7A (NM_000260.3) results in a phenotype consistent with Usher syndrome type III [Liu et al 1998a].DFNA11. Mutations in MYO7A have also been shown to cause autosomal dominant nonsyndromic hearing loss (DFNA11) [Tamagawa et al 2002] (see Deafness and Hereditary Hearing Loss Overview). A unique putative dominant-negative mutation in the coiled-coil domain necessary for myosin-7a homodimer formation has been seen in related individuals segregating autosomal dominant nonsyndromic hearing loss (DFNA11).DFNB2. Mutations in MYO7A associated with autosomal recessive nonsyndromic hearing loss (DFNB2) have been reported [Hildebrand et al 2010]. However, a reanalysis of the phenotype in one large DFNB2 pedigree revealed the presence of retinitis pigmentosa (RP), indicating that the affected individuals in fact have USH1B (not DFNB2), reinforcing the multidisciplinary approach needed to make an accurate diagnosis of Usher syndrome [Zina et al 2001].USH1CContiguous gene deletion syndrome. A contiguous gene deletion including the USH1C locus causes infantile hyperinsulinism, enteropathy, and deafness [Bitner-Glindzicz et al 2000].DFNB18. See Deafness and Hereditary Hearing Loss Overview. Mutations in USH1C have also been shown to cause autosomal recessive nonsyndromic hearing loss (DFNB18) [Ahmed et al 2002, Ouyang et al 2002]. A genotype-phenotype correlation has been proposed by the observation of less deleterious mutations in USH1C in individuals from a family defining the DFNB18 locus or from simplex cases (i.e., single occurrences in a family) of deafness without RP [Ahmed et al 2002, Ouyang et al 2002].CDH23DFNB12. See Deafness and Hereditary Hearing Loss Overview. Missense mutations in CDH23 have also been shown to cause autosomal recessive nonsyndromic hearing loss (DFNB12) [Bork et al 2001, Astuto et al 2002, Bork et al 2002].PCHD15DFNB23. As is seen in USH1D/DFNB12 with CDH23 mutations and USH1C/DFNB18 with USH1C mutations, missense mutations in PCDH15 have been found to cause DFNB23 [Ahmed et al 2008, Doucette et al 2009], while more severe mutations (splicing, frameshift, nonsense, large deletions) cause USH1F.}

Natural HistoryThe hearing loss in Usher syndrome type I is congenital (i.e., present at birth), bilateral, and profound. Affected individuals do not develop speech. Vestibular areflexia is associated with the deafness and is a defining feature of this disorder. Because of vestibular areflexia, children with Usher syndrome type I typically walk later than usual, at approximately age 18 months to two years. Older children may seem 'clumsy' and experience frequent accidental injuries or have difficulty with activities requiring balance, such as riding a bicycle or playing sports.The child with Usher syndrome type I is often misdiagnosed as having nonsyndromic deafness until tunnel vision and night blindness, early signs of retinitis pigmentosa, become severe enough to be noticeable, either by parents and teachers or by the individual. RP is progressive, bilateral, symmetric degeneration of the retina that initiates at the periphery; rods (photoreceptors active in the dark-adapted state) are mainly affected first, causing night blindness and constricted visual fields (tunnel vision). Cones (photoreceptors active in the light-adapted state) may also be involved [Gregory-Evans & Bhattacharya 1998].Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees is common for a person with Usher syndrome type I who is age 30-40 years. Visual impairment worsens significantly each year [Pennings et al 2004]. However, it is unusual for the typical individual with Usher syndrome type I to become completely blind, although cataracts sometimes reduce central vision to light/dark perception only.Heterozygotes. Heterozygotes are asymptomatic; however, they may exhibit slightly subnormal electrooculographies (EOGs) and audiograms that are not sensitive or specific enough for carrier detection. Note: The EOG is an electrophysiologic test of function of the oculomotor system. Electrodes are placed on each side of the eye; the individual being tested keeps the head still, while moving his/her eyes back and forth, alternating between two flashing red lights. The EOG is redundant with the ERG in most retinal disorders. The advantage of the EOG, however, is that the electrodes do not touch the surface of the eye.

Genotype-Phenotype CorrelationsCDH23. A clear genotype-phenotype correlation exists in persons with CDH23 mutations with respect to hearing loss, vestibular findings, and RP. A reduced frequency of null (e.g., nonsense, frameshift, splice) mutations in CDH23 is observed as the phenotype becomes milder, with approximately 88%, 67%, and 0% of null mutations found in persons with typical Usher type 1, atypical Usher type 1, and DFNB18, respectively [Astuto et al 2002].

Differential DiagnosisNonsyndromic hearing loss. Often, a family with more than one affected sib is thought to have nonsyndromic hearing loss (NSHL) (see Deafness and Hereditary Hearing Loss Overview) until the oldest is diagnosed with retinitis pigmentosa (RP). Subsequent visual evaluation often reveals the presymptomatic early stages of RP in younger affected sibs. Mutations for NSHL and RP can be inherited independently by a single individual whose symptoms mimic those of Usher syndrome. NSHL and RP are both relatively common, with frequencies of 1:1000 and 1:4000, respectively. Larger families lessen the statistical probability of this occurrence, because at least one sib is likely to inherit one mutation without the other.Usher syndrome type II. Usher syndrome type II is characterized by (1) congenital, bilateral sensorineural hearing loss predominantly in the higher frequencies that ranges from mild to severe; (2) normal vestibular function; and (3) adolescent-to-adult onset of retinitis pigmentosa. One of the most important clinical distinctions between Usher syndrome type I and Usher syndrome type II is that children with Usher syndrome type I are usually delayed in walking until age 18 months to two years because of vestibular involvement, whereas children with Usher syndrome type II usually begin walking at approximately age one year.Usher syndrome type III. Usher syndrome type III is characterized by postlingual progressive sensorineural hearing loss, late-onset RP, and variable impairment of vestibular function [Plantinga et al 2005]. Mutations in USH3 are causative [Fields et al 2002, Aller et al 2004]. Some individuals with Usher syndrome type III may have profound hearing loss and vestibular disturbance and thus be clinically misdiagnosed as having Usher syndrome type I [Pennings et al 2003].Deafness-dystonia-optic neuronopathy (DDON). Males with deafness-dystonia-optic neuronopathy (DDON) syndrome have prelingual or postlingual sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment appears to be constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia. Mutations in TIMM8A are causative. Inheritance is X-linked.Individuals with DDON syndrome may initially be suspected of having Usher syndrome [Kimberling W, personal communication, 2005] because the hearing impairment in DDON syndrome may be congenital and the hearing impairment in Usher syndrome type II may be progressive [Sadeghi et al 2004].Other. Viral infections, diabetic neuropathy, and syndromes involving mitochondrial defects (see Mitochondrial Disorders Overview) can all produce concurrent symptoms of hearing loss and retinal pigmentary changes that suggest Usher syndrome.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Usher syndrome type I, the following evaluations are recommended:Audiology. Otoscopy, puretone audiometry, assessment of speech perception, and, in some cases, auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE)Vestibular function. Rotary chair, calorics, electro-nystagmography, and computerized posturographyOphthalmology. Funduscopy, visual acuity, visual field (Goldmann perimetry), electroretinography (ERG)Treatment of ManifestationsHearing. Hearing aids are usually ineffectual in individuals with Usher syndrome type I because of the severity of the hearing loss.Cochlear implantation should be seriously considered, especially for young children [Damen et al 2006, Pennings et al 2006, Liu et al 2008].Communication skills may be optimized if all family members as well as affected children receive specialized training from educators of the hearing impaired.Balance. Tunnel vision and night blindness can combine with vestibular areflexia to predispose patients to accidental injury.Well-supervised sports activities may help a person with Usher syndrome type I to compensate by becoming more adept at using the somatosensory component of the balance system.Vision. See Retinitis Pigmentosa Overview, Management.Communication by sign language and lip reading becomes increasingly difficult over time as the RP progresses. Vision loss may progress to the point that the individual with Usher syndrome type I can only communicate through tactile signing.SurveillanceRoutine ophthalmologic evaluation is recommended to detect potentially treatable complications such as cataracts.Agents/Circumstances to AvoidCompetition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous.Persons with Usher syndrome type I often become disoriented when submerged in water because they lack the sense of where 'up' is; they should therefore exercise caution while swimming.Progressive loss of peripheral vision impairs the ability to safely drive a car.Evaluation of Relatives at RiskIt is appropriate to evaluate the hearing of all sibs at risk for Usher syndrome type I with ABR or DPOAE as soon after birth as possible to allow early diagnosis and treatment of hearing impairment.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherHearing aids are usually ineffectual in individuals with Usher syndrome type I because of the severity of the hearing loss.Vitamin A supplements. Although treatment with vitamin A palmitate may limit the progression of RP in persons with isolated RP and Usher syndrome type II, no studies have evaluated the effectiveness of vitamin A palmitate in individuals with Usher syndrome type I. Vitamin A is fat-soluble and not excreted in the urine. Therefore, high-dose vitamin A dietary supplements should be used only under the direction of a physician because of the need to monitor for harmful side effects such as hepatotoxicity. Of note, the studies by Berson et al [1993] were performed on individuals older than age 18 years because of the unknown effects of high-dose vitamin A on children.Lutein supplements. Oral administration of lutein (20 mg/d) for seven months had no effect on central vision; however, long-term effects are unknown [Aleman et al 2001].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Usher Syndrome Type I: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDUSH1BMYO7A11q13​.5Myosin-VIIaDeafness Gene Mutation Database
Hereditary Hearing Loss Homepage
Retina International Mutations of the Myosin VIIa Gene
CCHMC - Human Genetics Mutation Database
MYO7A @ LOVDMYO7AUSH1CUSH1C11p15​.1HarmoninThe USH1C mutations database
Deafness Gene Mutation Database
USH1C @ USHbases
Retina International Mutations of the Harmonin Gene (USH1C)
CCHMC - Human Genetics Mutation DatabaseUSH1CUSH1DCDH2310q22​.1Cadherin-23Deafness Gene Mutation Database
CDH23 @ USHbases
Hereditary Hearing Loss Homepage
Retina International Mutations of the Cadherin-related Protein 23 Gene (CDH23)
CCHMC - Human Genetics Mutation DatabaseCDH23USH1EUnknown21q21​.3Unknown USH1FPCDH1510q21​.1Protocadherin-15Deafness Gene Mutation Database
Retina International Mutations of the Protocadherin 15 Gene (PCDH15)
CCHMC - Human Genetics Mutation Database
PCDH15 @ LOVDPCDH15USH1GUSH1G17q25​.1Usher syndrome type-1G proteinRetNet: Genes and Mapped Loci Causing Retinal Diseases
CCHMC - Human Genetics Mutation Database
USH1G @ LOVDUSH1GUSH1HUSH1H15q22-q23Unknown USH1HUSH1JCIB215q25​.1Calcium and integrin-binding family member 2 CIB2USH1KUnknown10p11​.21-q21.1Unknown Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Usher Syndrome Type I (View All in OMIM) View in own window 276900USHER SYNDROME, TYPE I; USH1 276903MYOSIN VIIA; MYO7A 276904USHER SYNDROME, TYPE IC; USH1C 601067USHER SYNDROME, TYPE ID; USH1D 602083USHER SYNDROME, TYPE IF; USH1F 602097USHER SYNDROME, TYPE IE; USH1E 605242USH1C GENE; USH1C 605514PROTOCADHERIN 15; PCDH15 605516CADHERIN 23; CDH23 605564CALCIUM- AND INTEGRIN-BINDING PROTEIN 2; CIB2 606943USHER SYNDROME, TYPE IG; USH1G 607696USH1G GENE; USH1G 612632USHER SYNDROME, TYPE IH; USH1H 614869USHER SYNDROME, TYPE IJ; USH1J 614990USHER SYNDROME, TYPE IK; USH1KMolecular Genetic PathogenesisThe five known USH1 proteins interact with one another, with the first PDZ domain of harmonin playing a central role in this network. If any one of the molecules in this "interactome" is nonfunctional or absent, sensoneuronal degeneration occurs in the inner ear and the retina. The USH2 proteins are also integrated into this network [Adato et al 2005, Reiners et al 2006, Maerker et al 2008]. Note: A comprehensive set of databases (UMD-USHbases) provides information about mutations responsible for Usher syndrome [Baux et al 2008].MYO7ANormal allelic variants. Kelley et al [1997] reported that MYO7A is relatively large (120 kb) and the largest transcript (7.4 kb) has 49 exons.Pathologic allelic variants. See Table A. Normal gene product. The myosin-7a protein belongs to a group of unconventional (non-muscle) myosins, which are ATP-driven motor molecules with structurally conserved heads and highly divergent tails that move along actin filaments and may be involved with intracellular transport mechanisms. In the region syntenic to 11q13 (mouse chromosome 7), mutations in mouse myo7a were shown in shaker-1 (sh1) mice; sh1 mice are deaf and have vestibular areflexia but no RP.Detailed molecular genetic and histologic examination of sh1 mice is helping to illuminate the role that myosin-7a plays in cochlear hair cell development and/or function. The stereociliary hair bundle at the top of the hair cell is filled with actin; myosin-7a is believed to be attached to the actin-rich network within the hair cell. Myosin-7a colocalizes with crosslinks that connect the shafts of stereocilia, suggesting that myosin-7a is required for structural organization of the hair cell bundles. Electron microscopy indicates that myosin-7a may anchor or control the stereocilia [Self et al 1998]. Major functional abnormalities in stereocilia that interfere with proper sound transduction were identified in two distinct sh-1 mutant mice [Kros et al 2002].The C-terminal FERM domain of myosin-7a binds to a novel transmembrane protein, vezatin (a component of adherens junctions) [Kussel-Andermann et al 2000] and harmonin b, which in turn binds to both cadherin-23 and the f-actin microfilaments, forming a protein complex in the stereocilia of hair cells [Boeda et al 2002]. In the eye, sh-1 mice had been examined for RP-like retinal degeneration by funduscopy, histology, and ERG, but no obvious sign of retinal anomalies resembling RP were detected. Subsequently, Liu et al [1998b] demonstrated with electron microscopy that mutant myosin-7a causes defective distribution of melanosomes in the shaker-1 retina, since melanosomes did not extend into the apical processes of the retinal pigment epithelium (RPE). Liu et al [1998b] theorized that melanosomes could be transported along the RPE apical processes by myosin-7a. Phagocytosis of photoreceptor outer segments and transport of the ingested disks to the base of RPE cells is abnormal in the sh-1 mouse [Gibbs et al 2003]. Libby & Steel [2001] found that ERGs of some strains of shaker mice are subnormal even though the fundus did not show any abnormality. The inner and outer segments of rod photoreceptors are joined by the connecting cilium and both opsin and myosin-7a were shown to colocalize within the ciliary membrane of this structure. Furthermore, actin was identified in the photoreceptor cilium, which is spatially colocalized with myosin-7a and opsin, suggesting that the actin cytoskeleton of the cilium may provide the structural bases for myosin-7a-linked trafficking of membrane components, including rhodopsin, from the inner to the outer segments [Wolfrum & Schmitt 2000].Abnormal gene product. See Molecular Genetic Pathogenesis.USH1CNormal allelic variants. USH1C is encoded by 28 exons with at least eight distinct transcripts found in mouse vestibule mRNA through the alternative use of eight exons (exon 15, exons A-G) and two alternate splice acceptors [Verpy et al 2000]. At least 31 single-base normal allelic variants have been reported [Zwaenepoel et al 2001]. One allele of a polymorphic 45-nucleotide variable number of tandem repeats c.496+59_496+103[9] present in intron 5 was found to be in complete linkage disequilibrium with an Acadian founder USH1C splicing mutation c.216G>A (see Table 2) [Savas et al 2002].Pathologic allelic variants. See Table A, Table 2. The first USH1C mutations identified include the Acadian founder mutation c.216G>A, which was shown to create a cryptic splice donor inside exon 3 affecting mRNA stability and usage of the normal exon 3 splice donor [Bitner-Glindzicz et al 2000].The most common USH1C mutation observed in persons from other ethnic origins is c.238dupC [Bitner-Glindzicz et al 2000, Verpy et al 2000, Zwaenepoel et al 2001, Ahmed et al 2002, Blaydon et al 2003, Ouyang et al 2003]. Outside the Acadian population of Louisiana, the total contribution of USH1C mutations to the Usher syndrome type 1 phenotype ranges from 1.65% to 12.5% [Blaydon et al 2003, Ouyang et al 2003].Table 2. Selected USH1C Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change Reference SequencesNormalc.496+59_496+103[9]No impact on proteinNM_005709​.3
NP_005700​.2Pathologicc.216G>A ^{1p.Val72Glufs*65c.238dupCp.Arg80Profs*69See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. G to A change in exon 3 created a new splice site resulted in 35 bp deletion of exon 3 [Bitner-Glindzicz et al 2000, Lentz et al 2005].Normal gene product. The harmonin protein (from harmonia, Greek for 'assembling') was the first member of a large and diverse group of PDZ-domain-containing proteins shown to be mutated in a human disorder; PDZ represents an acronym for the first proteins recognized with these interaction domains: PSD-95, Discs-large, and ZO-1 [Hung & Sheng 2002]. PDZ domain proteins have functions in localizing and organizing the assembly of larger protein complexes at the plasma membrane for functions such as signal transduction, cell adhesion, and subcellular transport [Hung & Sheng 2002]. There are three isoform classes of harmonin, named a, b and c, depending on the number of PDZ and coiled-coiled domains and the presence or absence of a PST (proline, serine, threonine-rich) domain. These three functional domains participate in protein-protein interactions, which are proposed to be important to its putative functions in the ear and eye. In most tissues, harmonin is expressed as isoform a and/or c. The domain structure of the long harmonin b isoform includes two PDZ domains, followed by two coiled-coil motifs, one proline-, serine-,and threonine-rich region (PST), and a third PDZ domain [Verpy et al 2000]. In the developing ear, harmonin b has been found within the differentiating hair cells and at the tip of the growing stereociliary bundle. In the mature adult ear, isoform b disappears, and isoforms a and c are found along the stereocilia and within the hair cell, particularly at the base of the stereocilia and at the synapse [Verpy et al 2000, Boeda et al 2002, Reiners et al 2006].In the eye, harmonin b does not appear to be present in the retina, but the other harmonin isoforms have been found in all compartments of the neural retina [Verpy et al 2000, Williams et al 2009]. Several binding studies have found an interaction between the Usher 1 proteins, suggesting that harmonin plays a central role in the network. The PDZ2 domain of harmonin has a high affinity for the intracellular COOH terminal PDZ-binding interface (PBI) of the USH1D gene product cadherin-23 [Boeda et al 2002, Siemens et al 2002]. The PDZ1 domain of harmonin b interacts with an internal PBI of cadherin-23, the tail portion of myosin-7a and USH1G protein, while the COOH half of harmonin b containing PZD3 bundles f-actin microfilaments [Boeda et al 2002, Siemens et al 2002, Weil et al 2003]. These data, along with the inner ear histology and physiology of the mouse mutants of myo7a, cdh23, sans, and possibly pdch15 implicate these proteins as forming a critical macromolecular complex necessary for the development of stereocilia structure and function [Boeda et al 2002].Abnormal gene product. See Molecular Genetic Pathogenesis.CDH23Normal allelic variants. Individuals with Usher syndrome type I who showed linkage to chromosome 10q21-q22 were found to have mutations in CDH23, a 70- exon gene encoding a member of the cadherin gene superfamily [Bolz et al 2001, Bork et al 2001, Di Palma et al 2001b]. Mutations in mouse cdh23 gene cause the deafness phenotype in waltzer mice [Di Palma et al 2001a]. Exon 1 (human) and exons 1-2 (mouse) are non-coding and in the CDH23 mutation literature, these exons are omitted from the exon numbering system; thus CDH23 is cited as a gene with 69 exons. At least 86 polymorphic or rare variants not believed to be pathologic have been characterized including 41 in the coding regions of CDH23 [Astuto et al 2002]. At least two normal isoforms of CDH23 exist in human and mouse and differ by the inclusion or exclusion of the 105-nucleotide exon 68 [Bork et al 2001, Di Palma et al 2001b]. The +68 isoform adds 35 amino acids to the intracellular tail of the cadherin-23 protein, which is inner-ear specific and important for its proposed role in the cochlea [Siemens et al 2002].Pathologic allelic variants. See Table A.Normal gene product. Cadherin-23 is a member of the superfamily of glycosylated transmembrane proteins known to be involved in cell-cell adhesion, cell sorting, and cell migration during development and in differentiated tissues. Cadherin extracellular domains have repeated and varying numbers of cadherin-like motifs (ectodomains) that form Ca2+-dependent lateral homophilic binding interactions. Cadherin-23 has 27 EC domains, one helical transmembrane domain and an intracellular tail having one internal and one COOH-terminal PDZ binding interface (PBI) [Siemens et al 2002]. Many of the missense mutations in CDH23 occur in the ectodomains disrupting putative Ca2+ binding sites, which may therefore affect proper tertiary structure and rigidity of the extracellular domain [Astuto et al 2002]. In the mouse, expression of cdh23 message was restricted to the inner and outer cochlear hair cells [Di Palma et al 2001a]. The PDZ2 domain of harmonin has a high affinity for the COOH terminal PBI of cadherin-23 [Boeda et al 2002, Siemens et al 2002]. The inner-ear-specific transcript +68 protein isoform was shown to disrupt binding of harmonin PDZ1 to an internal PBI by the addition of 35 amino acids, suggesting a tissue-specific difference in the interaction between cadherin-23 and harmonin in the inner ear and retina [Siemens et al 2002]. Cadherin-23 makes up the upper part of the tip links of the hair cell stereocilia and directly binds to the tail of myosin VIIa. These two proteins together with harmonin form a ternary complex; thus, it is likely that myosin VIIa applies tension forces on the hair bundle links [Bahloul et al 2010].Abnormal gene product. See Molecular Genetic Pathogenesis.PCDH15Normal allelic variants. Human PCDH15 on chromosome 10q21-q22 has 33 exons, with the start codon residing in the second exon; PCDH15 was implicated as the USH1F-related gene by the observation of orthologous mouse mutations in the Ames waltzer deafness mouse [Alagramam et al 2001a]. Pathologic allelic variants. See Table A, Table 3. Large deletions within PCDH15 may be a significant cause of USH1F [Le Guédard et al 2007].The Ashkenazi Jewish founder mutation c.733C>T has a carrier frequency in the Jewish population (0.79%-2.48%) similar to that for other genetic disorders for which routine screening is performed in this population, including Tay-Sachs disease (3%-4%), Gaucher disease (4%-6%), and Canavan disease (1%-2%) [Ben-Yosef et al 2003].Table 3. Selected PCDH15 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.733C>Tp.Arg245XNM_033056​.3
NP_149045​.3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. Protocadherins are a large family of non-classic cadherins that are structurally and functionally divergent from the classic cadherins. The functions of some members include planar polarity determination, neural development, neural circuit formation, and formation of the synapse. Protocadherin 15 is a putative cell surface integral membrane protein having 11 extracellular cadherin-like ectodomains, one transmembrane domain, and a cytoplasmic domain containing two proline-rich regions. Immunohistochemistry shows protocadherin 15 localized to distinct structures in the developing mouse inner ear and human retina, as well as expression of mRNA from several adult human tissues including brain, lung, spleen, and kidney [Alagramam et al 2001b]. Because the earliest defects observed in Ames waltzer mice are morphologic stereociliary bundle defects, including bundles rotated up to 90° from the normal orientation, it has been suggested that protocadherin 15 may participate in the development of planar polarity of stereocilia organization on the apical surface of hair cells and is therefore similar in function to other non-classic cadherins [Alagramam et al 2001b, Raphael et al 2001]. In particular, protocadherin 15 is specifically associated with the tip-links that connect the stereocilia [Ahmed et al 2006].Abnormal gene product. See Molecular Genetic Pathogenesis.USH1GNormal allelic variants. USH1G, previously known as SANS, was identified by linkage analysis and candidate gene mutation screening from the chromosome 17q24-q25 region [Weil et al 2003]. USH1G comprises three exons; the last exon only codes for the TAA stop codon. No normal allelic variants have been reported for the gene. Pathologic allelic variants. See Table A, Table 4. Two mutations were identified in the homozygous state; p.Ser278Profs*71 is a 20-nucleotide deletion found in the original consanguineous Palestinian family that defined the linkage of USH1G to chromosome 17q [Mustapha et al 2002]. The second mutation was a p.Val132Glyfs*3 from a large consanguineous Tunisian family important in refining the location of USH1G [Weil et al 2003]. Two additional USH1G mutations were identified in affected brothers of a German family after screening 39 USH1 cases, of which 19 were negative for MYO7A and USH1C mutations and another six were excluded from being linked to MYO7A [Weil et al 2003].The mouse ortholog, ush1g, was shown to be the gene in which mutation results in the Jackson shaker deafness mouse [Kikkawa et al 2003].Table 4. Selected USH1G Pathologic Allelic Variants View in own windowDNA Nucleotide Change
(Alias 1) Protein Amino Acid Change Reference Sequencesc.394dupG
(c.393insG)p.Val132Glyfs*3NM_033056​.3
NP_149045​.3c.832_851del
(c.828-849del20)p.Ser278Profs*71NM_173477​.2
NP_775748​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. USH1G encodes a novel protein of 461 amino acids with three ankyrin (Ank) repeats and a sterile alpha motif (SAM) domain near the NH2- and COOH-termini, respectively [Kikkawa et al 2003, Weil et al 2003]. High expression levels were localized to the inner and outer hair cells. The function of proteins with similarity to Usher syndrome type-1G protein (also known as Sans) suggests a role either in postsynaptic specialization or as an anchoring/scaffolding protein in hair cells [Kikkawa et al 2003]. In cotransfection experiments, the PDZ1 domain of harmonin interacted with the PBI carboxy-terminus of Sans, suggesting that Sans is another macromolecular component made of proteins defective both in Usher syndrome type 1 (USH1B, USH1C, USH1D, USH1F, USH1G) and in mouse models of inherited deafness (shaker-1, waltzer, Ames waltzer, Jackson shaker), which is necessary for proper development and maintenance of the stereocilia of hair cells [Weil et al 2003, Yan et al 2010].Abnormal gene product. See Molecular Genetic Pathogenesis.}