Clinical Diagnosis

A diagnosis of Usher syndrome type II (USH2) requires the following:

• Congenital (i.e., prelingual) sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies (see Deafness and Hereditary Hearing Loss Overview)
• Intact vestibular responses
• Retinitis pigmentosa (RP)
• Normal general health and intellect; otherwise normal physical examination
• A family history compatible with autosomal recessive inheritance

Molecular Genetic Testing

Genes. Subtypes of Usher syndrome type II and associated genes:

• Usher syndrome type 2A. Alterations in USH2A account for approximately 80% of all Usher syndrome type II
• Usher syndrome type 2C. Alterations in GPR98 (previously known as VLGR1) [Weston et al 2004]
• Usher syndrome type 2D. Alterations in DFNB31 [Ebermann et al 2007]

Evidence for further locus heterogeneity

• USH2B. Hmani-Aifa et al [2009] provide evidence that the USH2B locus does not exist; mutations in GPR98 have now been found in the Tunisian family originally used to map USH2B.
• A fourth locus associated with Usher syndrome type II has been provisionally mapped to 15q in a consanguineous Tunisian family [Ben Rebeh et al 2008].

Clinical testing

• Sequence analysis
  • USH2A. Sequence analysis of exons 1-21 of USH2A and flanking intronic regions identified one or two mutations in 35% to 65% of individuals with clinical findings consistent with Usher syndrome type II [Ouyang et al 2004, Pennings et al 2004b, Seyedahmadi et al 2004, van Wijk et al 2004, Bernal et al 2005, Maubaret et al 2005]. Exon 21 is alternatively spliced, giving rise to both short and long isoforms. Analysis of exons 22-72 identified a homozygous mutation in one patient and a second mutation in 14 of 24 Spanish patients previously shown to have a mutation in the first 21 exons [Aller et al 2006]. Analysis of all 73 exons in Scandinavian individuals identified one or two mutations in 75% [Dreyer et al 2008].
  • GPR98 (USH2C). Sequence analysis identified four mutations in GPR98 in individuals from three multiplex families and in two individuals who represent simplex cases of Usher syndrome type 2C [Weston et al 2004].
  • DFNB31 (USH2D). Sequence analysis of DFNB31 identified a nonsense mutation in exon 1 and an exon 2 splice donor site mutation in people with USH2 from a German family [Ebermann et al 2007].
• Deletion/duplication analysis
  • USH2A. Dreyer et al [2008] reported numerous mutations in USH2A including a multiexonic deletion involving exons 21-32.
  • GPR98. Hilgert et al [2009] reported a large deletion g.371657_507673del of exons 84 and 85.

Table 1. Summary of Molecular Genetic Testing Used in Usher Syndrome Type II (USH2)

View in own window

Gene Symbol (Locus)	Percent of Usher Syndrome Type II	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
USH2A (USH2A)	80%	Sequence analysis	Sequence variants 2	~35%-75% 3	Clinical
		Deletion/ duplication analysis 4	Exonic or whole-gene deletions	Unknown
GPR98 (USH2C)	~15%	Sequence analysis	Sequence variants 2	Unknown	Clinical
		Deletion / duplication analysis 4	Exonic or whole-gene deletions	Unknown
DFNB31 (USH2D)	<5%	Sequence analysis	Sequence variants 2	Unknown	Clinical
		Deletion/ duplication analysis 4	Exonic or whole-gene deletions 5

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Frequency of detecting one or both mutant alleles in USH2A

4. 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. See array GH.

5. No deletions or duplications involving DFNB31 have been reported to cause Usher syndrome type 2D. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing the diagnosis in a proband. If the clinical findings are compatible with the diagnosis of Usher syndrome 2, to confirm/establish the diagnosis, the order of molecular genetic testing is as follows:

1.

Sequence analysis of USH2A

2.

Deletion/duplication analysis of USH2A

3.

Sequence analysis of GPR98 (USH2C)

4.

Deletion/duplication analysis of GPR98 (USH2C)

5.

Sequence analysis of DFNB31 (USH2D)

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

USH2A. Mutations in USH2A are also a common cause of nonsyndromic autosomal recessive retinitis pigmentosa (arRP). (See Retinitis Pigmentosa Overview.) Seyedahmadi et al [2004] found USH2A mutations in 12% of individuals with arRP.

Rivolta et al [2000] observed a novel USH2A missense mutation, p.Cys759Phe, in individuals with arRP; many of these individuals had normal hearing even when their second mutation was known to be associated with Usher syndrome type II (including the common p.Glu767SerfsX21 mutation). However, homozygosity of p.Cys759Phe in unaffected individuals indicates that this mutation may not be sufficient to cause arRP [Bernal et al 2003]. This mutation was not found in Israeli individuals with arRP, but compound heterozygotes for an USH2A mutation and other novel sequence changes in exons 22-72 were reported, in particular for p.Arg4674Gly [Kaiserman et al 2008].

GPR98 (VLGR1). A nonsense mutation in GPR98 was found in one of 48 families with febrile seizures [Nakayama et al 2002], suggesting that such mutations are unlikely to be a common cause of febrile seizures in humans. However, the Frings mouse, which is prone to audiogenic seizures, has a spontaneous mutation in Vlgr1 [Skradski et al 2001].

DFNB31. Mutations in DFNB31 are also associated with nonsyndromic autosomal recessive hearing loss [Mburu et al 2003, Tlili et al 2005].

Natural History

The hearing loss in Usher syndrome type II (USH2) is congenital and bilateral, occurring predominantly in the higher frequencies and ranging from mild to severe. The degree of hearing loss varies within and among families; however, the 'sloping' audiogram is characteristic of Usher syndrome type II. The hearing loss may be perceived by the affected individual as progressing over time because speech perception decreases. This perception may be caused by diminished vision that interferes with subconscious lip reading.

The clinical picture of Usher syndrome type II is complicated; subtle variations within the Usher syndrome type II hearing phenotype have been observed in several Dutch studies. In the first, three of 13 persons with Usher syndrome type II had a mild but definite progression of hearing loss unrelated to presbycusis; these three families showed linkage to USH2A and not to USH3, the locus associated with Usher syndrome type III. A subsequent cross-sectional study of 27 persons with Usher syndrome type 2A confirmed by linkage analysis compared hearing threshold against age; significant progression of hearing impairment was observed but at a much slower rate than reported for Usher syndrome type III [Pennings et al 2003]. In contrast, in a large study of 125 individuals with Usher syndrome type II, Reisser et al [2002] found no clinically relevant hearing loss over a span of up to 17 years.

To help resolve these differences, Sadeghi et al [2004] compared serial audiograms of individuals with the USH2A phenotype (group 1) with those of individuals with a non-USH2A Usher syndrome type II phenotype (group 2). They found significantly worse thresholds in group 1 than in group 2 after the second decade. Also, in group 1, progression started earlier and was more pronounced than in group 2. These results suggest that the USH2A auditory phenotype may be different from that of other subtypes of Usher syndrome type II.

Retinitis pigmentosa (RP) is a 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 continue to narrow throughout life, but the rate and degree of loss among individuals vary greatly between and within families. A visual field of five to ten degrees is common for a person with Usher syndrome type II age 30-40 years. Visual impairment increases significantly each year [Iannaccone et al 2004, Pennings et al 2004a]. However, it is unusual for the typical individual with Usher syndrome type II to become completely blind, although cataracts sometimes reduce central vision to light/dark perception only.

RP age of onset as well as tooth-enamel dysplasia may be subtle clinical indicators that can be used in conjunction with linkage analysis to subtype families with Usher syndrome type II on a research basis. Enamel defects were also reported in a child with Usher syndrome type I [Balmer & Fayle 2007].

Heterozygotes. Heterozygotes are asymptomatic; however, they may exhibit:

• Audiograms that are not sensitive or specific enough for carrier detection
• Slightly subnormal electrooculographies (EOGs). The clinical EOG is an electrophysiologic test of function of the oculomotor system. Electrodes are placed on each side of the eye, and the patient, while keeping the head still, moves his or 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 Correlations

Bernal et al [2005] performed ophthalmologic, vestibular, and audiometric examinations of affected individuals in 13 Spanish families with USH2A; in eight families, both mutations were identified and in five, only one was identified. No genotype-phenotype correlations were observed within or between families.

Schwartz et al [2005] did not observe any genotype-phenotype correlations between individuals with mutations in USH2A and those with mutations in GPR98; however, only three sibs with mutations in GPR98 were evaluated. They found a wide spectrum of photoreceptor disease with more rod than cone dysfunction, and both intra- and interfamilial variation for Usher syndrome type 2A.

Nomenclature

USH2B. Hmani-Aifa et al [2009] provide evidence that the USH2B locus does not exist; mutations in GPR98 (USH2C) have now been found in the Tunisian family originally used to map USH2B.

Prevalence

The prevalence of Usher syndrome in the general US population has been conservatively estimated at 4.4:100,000; the carrier frequency may be as high as 1:70.

The prevalence of Usher syndrome in persons of Scandinavian descent has been estimated at around 3.6:100,000.

Usher syndrome has been estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness.

The above estimates were made prior to 1989, when Möller et al [1989] subdivided Usher syndrome into Usher syndrome type I (USH1) and type II (USH2), and before the recognition of Usher syndrome type III (USH3). The specialized educational requirements of the congenitally deaf have historically rendered the population with USH1 more accessible for study by researchers. Persons with USH2 or USH3 communicate orally and are mainstreamed into regular schools; thus, the prevalence of USH2 and USH3 in the general population cannot be estimated as accurately as that of USH1. Often, persons with USH2 are not diagnosed until early adulthood, when progressive RP becomes debilitating. The true prevalence of USH2 in the general population is not currently known.

More recently, the prevalence of Usher syndrome in Heidelberg, Germany and its suburbs has been calculated to be 6.2:100,000 [Spandau & Rohrschneider 2002]. In that study, the ratio of USH1 to USH2 was 1:3.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Usher syndrome type II (USH2), 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 oto-acoustic emission (DPOAE)
• Vestibular function. Rotary chair, calorics, electronystagmography, and computerized posturography
• Ophthalmology. Funduscopy, visual acuity, visual field (Goldmann perimetry), electroretinography (ERG)

Treatment of Manifestations

Hearing. Hearing aids are helpful. Young children can benefit from early fitting of hearing aids and speech training to normalize language.

Environmental trauma (e.g., noise) or a genetic susceptibility (e.g., presbycusis) in addition to the congenital, stable deficit of USH2 may combine to produce severe-to-profound hearing loss in older individuals with USH2; in such cases, cochlear implantation may be warranted.

Vision. See Retinitis Pigmentosa Overview: Management.

Tunnel vision and night blindness can increase the likelihood of accidental injury.

Surveillance

Routine auditory evaluation is recommended in order to detect changes that may require modifications to hearing aids.

Routine ophthalmologic evaluation is recommended in order to detect potentially treatable complications such as cataracts.

Agents/Circumstances to Avoid

Competition in various sports requiring a full range of vision may be difficult and possibly dangerous.

Progressive loss of peripheral vision impairs the ability to safely drive a car.

Evaluation of Relatives at Risk

It is appropriate to evaluate the hearing of all sibs at risk for Usher syndrome type II with ABR or DPOAE as soon after birth as possible.

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Other

Vitamin A supplements. Although treatment with vitamin A palmitate may limit the progression of RP in some persons, no formal studies have evaluated its effectiveness in Usher syndrome type II. Vitamin A is fat soluble and not excreted in the urine. Therefore, high-dose vitamin A 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 six months had no effect on central vision; however, long-term effects are unknown [Aleman et al 2001].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Usher syndrome type II (USH2) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an individual with USH2 are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation in an USH2-related gene.
• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an affected individual are obligate heterozygotes.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is available on a clinical basis once the mutations in USH2A have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for Usher syndrome type 2A, 2C, and 2D is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as Usher syndrome are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The five known USH1 proteins and the three known USH2 proteins interact with one another; the first PDZ domain of harmonin plays 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 [Adato et al 2005, Reiners et al 2006, van Wijk et al 2006, Maerker et al 2008].

The protein encoded by GPR98 (VLGR1) belongs to a subgroup of the large N-terminal family B seven-transmembrane receptors, all of which have a G-protein-coupled proteolysis site. The proteins encoded by USH2A and GPR98 have quite similar pentraxin (PTX) homology domains, suggesting that they may share an affinity for a common binding partner. Also, the motif architecture of the protein encoded by VLGR1 is very like that of cadherins, two of which are encoded by genes associated with Usher type I (CDH23 and PCDH15). The very large extracellular portion of VLGR1b has 35 CalX-β modules, and the C-terminal residues correspond to the consensus motif for a PDZ-binding domain.

Note that a comprehensive set of databases (UMD-USHbases) providing information about mutations responsible for Usher syndrome is available [Baux et al 2008]. In addition, an Usher syndrome genotyping microarray based on the arrayed primer extension (APEX) method has been developed [Cremers et al 2007].

Published Guidelines/Consensus Statements

1. American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. (pdf) Available at www​.acmg.net. 2002. Accessed 12-27-11. [PMC free article: PMC3110944] [PubMed: 12180152]
2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available at genetics​.faseb.org. 2000. Accessed 12-29-11.

Literature Cited

1. Adato A, Lefèvre G, Delprat B, Michel V, Michalski N, Chardenoux S, Weil D, El-Amraoui A, Petit C. Usherin, the defective protein in Usher syndrome type IIA, is likely to be a component of interstereocilia ankle links in the inner ear sensory cells. Hum Mol Genet. 2005;14:3921–32. [PubMed: 16301217]
2. Adato A, Weston MD, Berry A, Kimberling WJ, Bonne-Tamir A. Three novel mutations and twelve polymorphisms identified in the USH2A gene in Israeli USH2 families. Hum Mutat. 2000;15:388. [PubMed: 10738000]
3. Aleman TS, Duncan JL, Bieber ML, de Castro E, Marks DA, Gardner LM, Steinberg JD, Cideciyan AV, Maguire MG, Jacobson SG. Macular pigment and lutein supplementation in retinitis pigmentosa and Usher syndrome. Invest Ophthalmol Vis Sci. 2001;42:1873–81. [PubMed: 11431456]
4. Aller E, Jaijo T, Oltra S, Alió J, Galán F, Nájera C, Beneyto M, Millán JM. Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability. Clin Genet. 2004;66:525–9. [PubMed: 15521980]
5. Aller E, Jaijo T, Beneyto M, Nájera C, Oltra S, Ayuso C, Baiget M, Carballo M, Antiñolo G, Valverde D, Moreno F, Vilela C, Collado D, Pérez-Garrigues H, Navea A, Millán JM. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet. 2006;43:e55. [PubMed: 17085681]
6. Aller E, Jaijo T, van Wijk E, Ebermann I, Kersten F, Garcia-Garcia G, Voesenek K, Aparisi MJ, Hoefsloot L, Cremers C, Diaz-Llopis M, Pennings R, Bolz H, Kremer H, Millán JM. Sequence variants of the DFNB31 gene among Usher syndrome patients of diverse origin. Mol Vis. 2010;16:495–500. [PMC free article: PMC2845667] [PubMed: 20352026]
7. Auslender N, Bandah D, Rizel L, Behar DM, Shohat M, Banin E, Allon-Shalev S, Sharony R, Sharon D, Ben-Yosef T. Four USH2A founder mutations underlie the majority of Usher syndrome type 2 cases among non-Ashkenazi Jews. Genet Test. 2008;12:289–94. [PubMed: 18452394]
8. Balmer R, Fayle SA. Enamel defects and ectopic eruption in a child with Usher syndrome and a cochlear implant. Int J Paediatr Dent. 2007;17:57–61. [PubMed: 17181580]
9. Baux D, Larrieu L, Blanchet C, Hamel C, Ben Salah S, Vielle A, Gilbert-Dussardier B, Holder M, Calvas P, Philip N, Edery P, Bonneau D, Claustres M, Malcolm S, Roux AF. Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients. Hum Mutat. 2007;28:781–9. [PubMed: 17405132]
10. Baux D, Faugère V, Larrieu L, Le Guédard-Méreuze S, Hamroun D, Béroud C, Malcolm S, Claustres M, Roux AF. UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes. Hum Mutat. 2008;29:E76–E87. [PubMed: 18484607]
11. Ben Rebeh I, Benzina Z, Dhouib H, Hadjamor I, Amyere M, Ayadi L, Turki K, Hammami B, Kmiha N, Kammoun H, Hakim B, Charfedine I, Vikkula M, Ghorbel A, Ayadi H, Masmoudi S. Identification of candidate regions for a novel Usher syndrome type II locus. Mol Vis. 2008;14:1719–26. [PMC free article: PMC2538493] [PubMed: 18806881]
12. Bernal S, Ayuso C, Antiñolo G, Gimenez A, Borrego S, Trujillo MJ, Marcos I, Calaf M, Del Rio E, Baiget M. Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation. J Med Genet. 2003;40:e8. [PMC free article: PMC1735247] [PubMed: 12525556]
13. Bernal S, Medà C, Solans T, Ayuso C, Garcia-Sandoval B, Valverde D, Del Rio E, Baiget M. Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype--phenotype correlation. Clin Genet. 2005;68:204–14. [PubMed: 16098008]
14. Berson EL, Rosner B, Sandberg MA, Hayes KC, Nicholson BW, Weigel-DiFranco C, Willett W. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111:761–72. [PubMed: 8512476]
15. Bhattacharya G, Kalluri R, Orten DJ, Kimberling WJ, Cosgrove D. A domain-specific usherin/collagen IV interaction may be required for stable integration into the basement membrane superstructure. J Cell Sci. 2004;117:233–42. [PubMed: 14676276]
16. Bhattacharya G, Miller C, Kimberling WJ, Jablonski MM, Cosgrove D. Localization and expression of usherin: a novel basement membrane protein defective in people with Usher's syndrome type IIa. Hear Res. 2002;163:1–11. [PubMed: 11788194]
17. Cremers FP, Kimberling WJ, Külm M, de Brouwer AP, van Wijk E, te Brinke H, Cremers CW, Hoefsloot LH, Banfi S, Simonelli F, Fleischhauer JC, Berger W, Kelley PM, Haralambous E, Bitner-Glindzicz M, Webster AR, Saihan Z, De Baere E, Leroy BP, Silvestri G, McKay GJ, Koenekoop RK, Millan JM, Rosenberg T, Joensuu T, Sankila EM, Weil D, Weston MD, Wissinger B, Kremer H. Development of a genotyping microarray for Usher syndrome. J Med Genet. 2007;44:153–60. [PMC free article: PMC2598068] [PubMed: 16963483]
18. Dreyer B, Brox V, Tranebjaerg L, Rosenberg T, Sadeghi AM, Möller C, Nilssen O. Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II. Hum Mutat. 2008;29:451. [PubMed: 18273898]
19. Dreyer B, Tranebjaerg L, Rosenberg T, Weston MD, Kimberling WJ, Nilssen O. Identification of novel USH2A mutations: implications for the structure of USH2A protein. Eur J Hum Genet. 2000;8:500–6. [PubMed: 10909849]
20. Ebermann I, Scholl HP, Charbel Issa P, Becirovic E, Lamprecht J, Jurklies B, Millán JM, Aller E, Mitter D, Bolz H. A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. Hum Genet. 2007;121:203–11. [PubMed: 17171570]
21. Ebermann I, Wiesen MH, Zrenner E, Lopez I, Pigeon R, Kohl S, Lowenheim H, Koenekoop RK, Bolz HJ. J Med Genet. 2009;46:277–80. [PubMed: 19357117]
22. Eudy JD, Weston MD, Yao S, Hoover DM, Rehm HL, Ma-Edmonds M, Yan D, Ahmad I, Cheng JJ, Ayuso C, Cremers C, Davenport S, Moller C, Talmadge CB, Beisel KW, Tamayo M, Morton CC, Swaroop A, Kimberling WJ, Sumegi J. Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa. Science. 1998;280:1753–7. [PubMed: 9624053]
23. Fields RR, Zhou G, Huang D, Davis JR, Möller C, Jacobson SG, Kimberling WJ, Sumegi J. Usher syndrome type III: revised genomic structure of the USH3 gene and identification of novel mutations. Am J Hum Genet. 2002;71:607–17. [PMC free article: PMC449697] [PubMed: 12145752]
24. Gregory-Evans K, Bhattacharya SS. Genetic blindness: current concepts in the pathogenesis of human outer retinal dystrophies. Trends Genet. 1998;14:103–8. [PubMed: 9540407]
25. Hilgert N, Kahrizi K, Dieltjens N, Bazazzadegan N, Najmabadi H, Smith RJ, Van Camp G. A large deletion in GPR98 causes type IIC Usher syndrome in male and female members of an Iranian family. J Med Genet. 2009;46:272–6. [PubMed: 19357116]
26. Hmani-Aifa M, Benzina Z, Zulfiqar F, Dhouib H, Shahzadi A, Ghorbel A, Rebai A, Soderkvist P, Riazuddin S, Kimberling WJ, Ayadi H. Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family. Eur J Hum Genet. 2009;17:474–82. [PMC free article: PMC2986209] [PubMed: 18854872]
27. Iannaccone A, Kritchevsky SB, Ciccarelli ML, Tedesco SA, Macaluso C, Kimberling WJ, Somes GW. Kinetics of visual field loss in Usher syndrome Type II. Invest Ophthalmol Vis Sci. 2004;45:784–92. [PubMed: 14985291]
28. Kaiserman I, Bahar I, Rootman DS. Optical coherence tomography provides insight into the effect of intacs in keratoconus. Arch Ophthalmol. 2008;126:571–2. [PubMed: 18413534]
29. Leroy BP, Aragon-Martin JA, Weston MD, Bessant DA, Willis C, Webster AR, Bird AC, Kimberling WJ, Payne AM, Bhattacharya SS. Spectrum of mutations in USU2A in British patients with Usher syndrome type II. Exp Eye Res. 2001;72:503–9. [PubMed: 11311042]
30. Liu X, Bulgakov OV, Darrow KN, Pawlyk B, Adamian M, Liberman MC, Li T. Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells. Proc Natl Acad Sci U S A. 2007;104:4413–8. [PMC free article: PMC1838616] [PubMed: 17360538]
31. Maerker T, van Wijk E, Overlack N, Kersten FF, McGee J, Goldmann T, Sehn E, Roepman R, Walsh EJ, Kremer H, Wolfrum U. A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum Mol Genet. 2008;17:71–86. [PubMed: 17906286]
32. Maubaret C, Griffoin JM, Arnaud B, Hamel C. Novel mutations in MYO7A and USH2A in Usher syndrome. Ophthalmic Genet. 2005;26:25–9. [PubMed: 15823922]
33. Mburu P, Mustapha M, Varela A, Weil D, El-Amraoui A, Holme RH, Rump A, Hardisty RE, Blanchard S, Coimbra RS, Perfettini I, Parkinson N, Mallon AM, Glenister P, Rogers MJ, Paige AJ, Moir L, Clay J, Rosenthal A, Liu XZ, Blanco G, Steel KP, Petit C, Brown SD. Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat Genet. 2003;34:421–8. [PubMed: 12833159]
34. McMillan DR, Kayes-Wandover KM, Richardson JA, White PC. Very large G protein-coupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system. J Biol Chem. 2002;277:785–92. [PubMed: 11606593]
35. Möller CG, Kimberling WJ, Davenport SL, Priluck I, White V, Biscone-Halterman K, Odkvist LM, Brookhouser PE, Lund G, Grissom TJ. Usher syndrome: an otoneurologic study. Laryngoscope. 1989;99:73–9. [PubMed: 2909824]
36. Nájera C, Beneyto M, Blanca J, Aller E, Fontcuberta A, Millán JM, Ayuso C. Mutations in myosin VIIA (MYO7A) and usherin (USH2A) in Spanish patients with Usher syndrome types I and II, respectively. Hum Mutat. 2002;20:76–7. [PubMed: 12112664]
37. Nakayama J, Fu YH, Clark AM, Nakahara S, Hamano K, Iwasaki N, Matsui A, Arinami T, Ptacek LJ. A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. Ann Neurol. 2002;52:654–7. [PubMed: 12402266]
38. Ouyang XM, Hejtmancik JF, Jacobson SG, Li AR, Du LL, Angeli S, Kaiser M, Balkany T, Liu XZ. Mutational spectrum in Usher syndrome type II. Clin Genet. 2004;65:288–93. [PubMed: 15025721]
39. Pearsall N, Bhattacharya G, Wisecarver J, Adams J, Cosgrove D, Kimberling W. Usherin expression is highly conserved in mouse and human tissues. Hear Res. 2002;174:55–63. [PubMed: 12433396]
40. Pennings RJ, Fields RR, Huygen PL, Deutman AF, Kimberling WJ, Cremers CW. Usher syndrome type III can mimic other types of Usher syndrome. Ann Otol Rhinol Laryngol. 2003;112:525–30. [PubMed: 12834121]
41. Pennings RJ, Huygen PL, Orten DJ, Wagenaar M, van Aarem A, Kremer H, Kimberling WJ, Cremers CW, Deutman AF. Evaluation of visual impairment in Usher syndrome 1b and Usher syndrome 2a. Acta Ophthalmol Scand. 2004a;82:131–9. [PubMed: 15043528]
42. Pennings RJ, Te Brinke H, Weston MD, Claassen A, Orten DJ, Weekamp H, Van Aarem A, Huygen PL, Deutman AF, Hoefsloot LH, Cremers FP, Cremers CW, Kimberling WJ, Kremer H. USH2A mutation analysis in 70 Dutch families with Usher syndrome type II. Hum Mutat. 2004b;24:185. [PubMed: 15241801]
43. Plantinga RF, Kleemola L, Huygen PL, Joensuu T, Sankila EM, Pennings RJ, Cremers CW. Serial audiometry and speech recognition findings in Finnish Usher syndrome type III patients. Audiol Neurootol. 2005;10:79–89. [PubMed: 15650299]
44. Reiners J, Nagel-Wolfrum K, Jürgens K, Märker T, Wolfrum U. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp Eye Res. 2006;83:97–119. [PubMed: 16545802]
45. Reisser CF, Kimberling WJ, Otterstedde CR. Hearing loss in Usher syndrome type II is nonprogressive. Ann Otol Rhinol Laryngol. 2002;111:1108–11. [PubMed: 12498372]
46. Rivolta C, Sweklo EA, Berson EL, Dryja TP. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet. 2000;66:1975–8. [PMC free article: PMC1378039] [PubMed: 10775529]
47. Sadeghi M, Cohn ES, Kelly WJ, Kimberling WJ, Tranebjoerg L, Moller C. Audiological findings in Usher syndrome types IIa and II (non-IIa). Int J Audiol. 2004;43:136–43. [PubMed: 15198377]
48. Schwartz SB, Aleman TS, Cideciyan AV, Windsor EA, Sumaroka A, Roman AJ, Rane T, Smilko EE, Bennett J, Stone EM, Kimberling WJ, Liu XZ, Jacobson SG. Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype. Invest Ophthalmol Vis Sci. 2005;46:734–43. [PubMed: 15671307]
49. Seyedahmadi BJ, Rivolta C, Keene JA, Berson EL, Dryja TP. Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. Exp Eye Res. 2004;79:167–73. [PubMed: 15325563]
50. Skradski SL, Clark AM, Jiang H, White HS, Fu YH, Ptácek LJ. A novel gene causing a mendelian audiogenic mouse epilepsy. Neuron. 2001;31:537–44. [PubMed: 11545713]
51. Spandau UH, Rohrschneider K. Prevalence and geographical distribution of Usher syndrome in Germany. Graefes Arch Clin Exp Ophthalmol. 2002;240:495–8. [PubMed: 12107518]
52. Tlili A, Charfedine I, Lahmar I, Benzina Z, Mohamed BA, Weil D, Idriss N, Drira M, Masmoudi S, Ayadi H. Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss. Hum Mutat. 2005;25:503. [PubMed: 15841483]
53. van Wijk E, Pennings RJ, te Brinke H, Claassen A, Yntema HG, Hoefsloot LH, Cremers FP, Cremers CW, Kremer H. 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. Am J Hum Genet. 2004;74:738–44. [PMC free article: PMC1181950] [PubMed: 15015129]
54. van Wijk E, van der Zwaag B, Peters T, Zimmermann U, Te Brinke H, Kersten FF, Märker T, Aller E, Hoefsloot LH, Cremers CW, Cremers FP, Wolfrum U, Knipper M, Roepman R, Kremer H. The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum Mol Genet. 2006;15:751–65. [PubMed: 16434480]
55. Weston MD, Eudy JD, Fujita S, Yao S, Usami S, Cremers C, Greenberg J, Ramesar R, Martini A, Moller C, Smith RJ, Sumegi J, Kimberling WJ, Greenburg J. Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa. Am J Hum Genet. 2000;66:1199–210. [PMC free article: PMC1288187] [PubMed: 10729113]
56. Weston MD, Luijendijk MW, Humphrey KD, Möller C, Kimberling WJ. Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II. Am J Hum Genet. 2004;74:357–66. [PMC free article: PMC1181933] [PubMed: 14740321]
57. Yang J, Liu X, Zhao Y, Adamian M, Pawlyk B, Sun X, McMillan DR, Liberman MC, Li T. Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss. PLoS Genetics. 2010;6:e1000955. [PMC free article: PMC2873905] [PubMed: 20502675]

Suggested Reading

1. Cohen M, Bitner-Glindzicz M, Luxon L. The changing face of Usher sydrome: Clinical implications. Int J Audiol. 2007;46:82–93. [PubMed: 17365059]

Acknowledgments

Edward Cohn, MD, Department of Otolaryngology, Boys Town National Research Hospital

Janos Sumegi, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha

Claes Möller, MD, PhD, Department of Otorhinolaryngology, Sahlgrenska University Hospital, Göteborg, Sweden

Research supported by FFB and NIH

Author History

Bronya Keats, PhD (2006-present)
William J Kimberling, PhD, FACMG; Boys Town National Research Hospital (1999-2006)
Jennifer Lentz, PhD (2006-present)
Dana J Orten, PhD; Boys Town National Research Hospital (2003-2006)
Sandra Pieke-Dahl, PhD; Ohio State University (1999-2003)
Michael D Weston, MA; Boys Town National Research Hospital (1999-2006)

Revision History

• 29 December 2011 (cd) Revision: deletion/duplication analysis available for GPR98 and DFNB31
• 23 December 2010 (me) Comprehensive update posted live
• 14 April 2009 (me) Comprehensive update posted live
• 5 November 2007 (cd) Revision: prenatal diagnosis for Usher syndrome type 2A available
• 14 November 2006 (me) Comprehensive update posted to live Web site
• 20 October 2004 (wk) Revision: sequencing of entire coding region available
• 13 January 2004 (wk) Revision: change in test availability
• 20 November 2003 (me) Comprehensive update posted to live Web site
• 10 December 1999 (me) Review posted to live Web site
• 19 February 1999 (wk) Original submission