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Usher Syndrome Type II

Synonym: USH2. Includes: USH2A, USH2C, USH2D

, PhD, FACMG and , PhD.

Author Information
, PhD, FACMG
Research School of Biology
Australian National University
Canberra, Australia
, PhD
Neuroscience Center
Louisiana State University Health Sciences Center
New Orleans, Louisiana

Initial Posting: ; Last Update: August 29, 2013.

Summary

Disease characteristics. Usher syndrome type II is characterized by congenital (i.e., prelingual) bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies, intact vestibular responses, and retinitis pigmentosa (RP). RP is progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity; the rate and degree of vision loss vary within and among families.

Diagnosis/testing. The diagnosis of Usher syndrome type II is established on clinical grounds using electrophysiologic and subjective tests of hearing and retinal function. Biallelic mutations in one of three genes are known to cause Usher syndrome type II: USH2A (accounting for up to 80% of cases), GPR98 (VLGR1), and DFNB31. A fourth locus has been provisionally mapped to 15q.

Management. Treatment of manifestations: Early fitting of hearing aids and speech training to normalize language.

Surveillance: Routine auditory evaluation to detect changes that may require modifications to hearing aids; routine ophthalmologic evaluation to detect potentially treatable complications such as cataracts.

Agents/circumstances to avoid: Tunnel vision and night blindness can increase the likelihood of accidental injury. Competition in 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: The hearing of at-risk sibs should be assessed as soon after birth as possible to allow early diagnosis and treatment of hearing loss.

Genetic counseling. Usher syndrome type II is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who has had a child with Usher syndrome type II has a 25% chance of resulting in an affected child, a 50% chance of resulting in an unaffected child who is a carrier, and a 25% chance of resulting in an unaffected child who is not a carrier. Prenatal testing is possible for pregnancies at increased risk if the disease-causing mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

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

Molecular Genetic Testing

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

  • Usher syndrome type 2A. Caused by alterations in USH2A; accounts 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

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

Gene Symbol /
Locus 1
Percent of Usher Syndrome Type II 2Test MethodMutations Detected 3
USH2A /
USH2A
57%-79%Sequence analysis / mutation scanning 4Sequence variants 5, 6
Deletion/duplication analysis 7Exonic or whole-gene deletions 8
Targeted mutation analysisSee footnote 9
GPR98 /
USH2C
6.6%-19%Sequence analysisSequence variants 5, 10
Deletion/duplication analysis 7Exonic or whole-gene deletions 11
Targeted mutation analysis See footnote 9
DFNB31 /
USH2D
0%-9.5%Sequence analysisSequence variants 5, 12
Deletion/duplication analysis 7Unknown, none reported 13
Targeted mutation analysis See footnote 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. Bonnet et al [2011], Le Quesne Stabej et al [2012], Garcia-Garcia et al [2013]

3. See Molecular Genetics for information on allelic variants.

4. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. 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 individual and a second mutation in 14 of 24 Spanish individuals 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].

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. Dreyer et al [2008] reported numerous mutations in USH2A including a multiexonic deletion involving exons 21-32.

9. Mutation panels may vary by laboratory.

10. 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].

11. Hilgert et al [2009] reported a large deletion of exons 84 and 85: g.371657_507673del.

12. 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].

13. No deletions or duplications involving DFNB31 have been reported to cause Usher syndrome type 2D.

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found in Bolz & Roux [2011] (full text).

Testing Strategy

To confirm/establish the diagnosis in a proband, the following testing strategies can be considered:

  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having Usher Syndrome 2 is single gene testing. The order of molecular genetic testing is as follows:
    • Sequence analysis of USH2A
    • Deletion/duplication analysis of USH2A
    • Sequence analysis of GPR98 (USH2C)
    • Deletion/duplication analysis of GPR98 (USH2C)
    • Sequence analysis of DFNB31 (USH2D)
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having Usher syndrome 2 is use of a multi-gene panel that simultaneously analyzes multiple genes associated with hereditary hearing loss.

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.

Clinical Description

Natural History

The hearing loss in Usher syndrome type II (USH2) is typically 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 USH2. 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.

Clinical variability of the hearing phenotype has been observed. In particular, a few individuals with USH2 have a mild but definite progression of hearing loss that is unrelated to presbycusis. A cross-sectional study of 27 persons with USH2A 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 progression of hearing loss over a span of up to 17 years.

Sadeghi et al [2004] compared serial audiograms of individuals with USH2 who had mutations in USH2A (group 1) with those of individuals diagnosed with USH2 who did not have mutations in USH2A (group 2). They found significantly worse thresholds in group 1 than in group 2 after the second decade. These results suggested that the USH2A auditory phenotype may be different from that of other subtypes of USH2. Abadie et al [2012], however, did not find any significant differences between the audiograms from 88 individuals with mutations in USH2A and ten individuals with mutations in GPR98.

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 show considerable intra- and interfamilial variation. 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.

Tooth enamel dysplasia. 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:

  • Audiogram anomalies 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 USH2A.

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. However, a study of children with hearing loss in Oregon found that 11% had mutations in genes associated with Usher syndrome and estimated that the prevalence may be as high as 1 in 6,000 [Kimberling et al 2010].

Usher syndrome has been estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. These 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 Usher syndrome type III (USH3) had not yet been recognized. 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 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.

Differential Diagnosis

Nonsyndromic hearing loss (NSHL). Often, a family with more than one affected sib is thought to have NSHL (see Deafness and Hereditary Hearing Loss Overview) until the oldest is diagnosed with RP (see Retinitis Pigmentosa Overview). Subsequent visual evaluation reveals the presymptomatic early stages of RP in younger affected sibs. Mutations in genes for NSHL and RP can be inherited independently by a single individual whose symptoms mimic those of Usher syndrome [Fakin et al 2012]. NSHL and RP are both relatively common, with frequencies at 1:1000 and 1:4000, respectively. Larger families lessen the statistical probability of this occurrence, because at least one sibling is likely to inherit one gene mutation without the other.

Usher syndrome type I (USH1). USH1 is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. One of the most important clinical distinctions between USH1 and USH2 is that children with USH1 are usually delayed in walking until age 18 months to two years because of vestibular involvement, whereas children with USH2 usually begin walking at approximately one year of age.

Usher syndrome type III (USH3). USH3 is characterized by postlingual progressive sensorineural hearing loss, late-onset RP, and variable impairment of vestibular function [Plantinga et al 2005]. Mutations in CLRN1 or HARS are causative [Joensuu et al 2001, Vastinsalo et al 2011, Puffenberger et al 2012]. Persons with USH3 may have symptoms that mimic USH2, especially early in the progression of the disease [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 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 because the hearing impairment in DDON syndrome may be congenital and the hearing impairment in Usher syndrome type II is occasionally progressive [Sadeghi et al 2004].

Other. Viral infections, diabetic neuropathy, and syndromes involving mitochondrial defects can all produce concurrent symptoms of hearing loss and RP.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 otoacoustic emission (DPOAE)
  • Vestibular function. Rotary chair, calorics, electronystagmography, and computerized posturography
  • Ophthalmology. Funduscopy, visual acuity, visual field (Goldmann perimetry), electroretinography (ERG)
  • Medical genetics consultation

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, as soon after birth as possible, to evaluate the hearing of all sibs at risk for Usher syndrome type II with ABR or DPOAE, and to perform molecular diagnostic testing if the disease-causing mutations have been identified in the affected family member.

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

Pregnancy Management

High-dose vitamin A supplementation should not be used by affected pregnant women, as large doses of vitamin A (doses above the RDA for pregnant or lactating women) may be teratogenic to the developing fetus (see Other).

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].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 individual with USH2 are obligate heterozygotes (carriers) for a disease-causing mutation.

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 possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating 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.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Coalition for Usher Syndrome Research
    c/o The Decibels Foundation
    1269 Main Street
    Concord MA 01742
    Phone: 617-951-9542
    Email: m.dunning@lek.com
  • National Library of Medicine Genetics Home Reference
  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    #2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Foundation Fighting Blindness
    11435 Cronhill Drive
    Owings Mills MD 21117-2220
    Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-568-0150
    Email: info@fightblindness.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • SENSE
    101 Pentonville Road
    London N1 9LG
    United Kingdom
    Phone: 0845 127 0060 (voice); 0845 127 0062 (textphone)
    Fax: 0845 127 0061
    Email: info@sense.org.uk
  • Usher Syndrome Registry
    Coalition for Usher Syndrome Research
    Phone: 617-951-9542
    Email: m.dunning@lek.com

Molecular Genetics

Information 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 II: Genes and Databases

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 II (View All in OMIM)

276901USHER SYNDROME, TYPE IIA; USH2A
602851G PROTEIN-COUPLED RECEPTOR 98; GPR98
605472USHER SYNDROME, TYPE IIC; USH2C
607928WHIRLIN; WHRN
608400USH2A GENE; USH2A
611383USHER SYNDROME, TYPE IID; USH2D

Molecular Genetic Pathogenesis

The six proteins associated with USH1 and the three proteins associated with USH2 interact with one another. Both harmonin (product of USH1C) and whirlin contain PDZ domains that play a role in these interactions. If any one of the molecules in this "Usher 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]. Another PDZ domain-containing protein, PDZD7, was identified as a result of a study of a child with nonsyndromic sensorineural hearing loss and a homozygous reciprocal translocation; protein-protein interaction studies indicated that PDZD7 is a part of the Usher protein network [Schneider et al 2009]. Mutations in PDZD7 have not yet been shown to cause Usher syndrome, but it has been suggested that PDZD7 mutations may act as modifiers of the retinal phenotype in individuals with USH2A. Additionally, an individual with USH2 and heterozygous mutations in USH2A and PDZD7 and another affected individual with heterozygous mutations in GPR98 and PDZD7 were reported, leading to the suggestion of digenic inheritance [Ebermann et al 2010].

Whirlin interacts in vivo with usherin and GPR98, suggesting that these three proteins function as a multi-protein complex in both the stereocilia of the cochlear hair cells and the periciliary membrane complex of the retinal photoreceptor cells [Yang et al 2010].

USH2A

Normal allelic variants. USH2A spans approximately 790 kb of genomic DNA and contains 72 exons [van Wijk et al 2004].

Pathologic allelic variants. More than 300 USH2A mutations have been documented. Initially it was thought that most mutations were in the 21 exons originally described, with p.Glu767Serfs*21 being the most common (16%) [Eudy et al 1998, Adato et al 2000, Dreyer et al 2000, Weston et al 2000, Leroy et al 2001, Nájera et al 2002]. However, many mutations have now been reported in exons 22-72 [Baux et al 2007] and in the flanking intronic sequences of all exons. A deep intronic mutation resulting in activation of a pseudoexon has also been found, indicating that RNA analysis should be done in individuals for whom only one mutation is identified by exome sequencing [Vaché et al 2012]. Four USH2A mutations account for 64% of mutant alleles underlying Usher syndrome type 2 in the non-Ashkenazi Jewish population [Auslender et al 2008]. Studies from China and Japan suggest that the spectrum of mutations may differ between Asian and European populations [Nakanishi et al 2011, Xu et al 2011].

Table 2. USH2A Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.2276G>Tp.Cys759PheNM_206933​.1
NP_996816​.1
c.2299delG 1p.Glu767Serfs*21
c.14020A>Gp.Arg4674Gly

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Associated with arRP (see Genetically Related Disorders)

Normal gene product. The 21 exons of USH2A originally described encode a protein of 1,546 amino acids. An additional 51 novel exons were subsequently identified, with the longest ORF extending from exon 2 to 72, and encoding a putative protein of 5,202 amino acids [van Wijk et al 2004]. Expression of both the short and long isoforms is highest in the adult retina, with the long form being the most predominant, and specifically localized to the photoreceptor cells. It is also found in developing cochlear hair cells, but disappears by about postnatal day 15 [Liu et al 2007].

The short isoform of usherin contains a secretion signal peptide, followed by four readily identifiable domains observed in extracellular matrix or cell adhesion proteins: a laminin G-like jellyroll fold, also found in thrombospondins and pentraxins (LamG/TSPN/PTX), laminin type VI (LN), ten laminin epidermal growth factor (LE), and four fibronectin type-III (FN3) repeats; the long isoform has an additional 28 FN3 repeats, as well as two laminin G (LamG) domains. It is predicted to have an outside-in transmembrane region followed by an intracellular domain that includes a PDZ-binding domain at its C-terminal end [van Wijk et al 2004]. Proteins with LamG/TSPN/PTX domains are involved in neuronal growth, patterning, and calcium-mediated ligand binding. The LN module of usherin has the most homology with the netrins, which are chemoattractant matrix molecules involved in nerve fiber guidance. Arrays of LE domains form rod-like tertiary structures that may provide a rigid spacer between two functional domains. FN domains in other proteins form beta-pleated sheets that bind heparin and integrin molecules. Usherin studies show colocalization with and binding to the extracellular basement membrane protein, type IV collagen, with a relatively broad tissue distribution [Bhattacharya et al 2002, Pearsall et al 2002, Bhattacharya et al 2004].

Abnormal protein product. See Molecular Genetic Pathogenesis.

The Ush2a knockout mouse model has stable moderate hearing loss and develops progressive photoreceptor degeneration after age ten months [Liu et al 2007].

GPR98 (VLGR1)

Normal allelic variants. GPR98 spans more than 600 kb of genomic DNA and contains 90 exons. It is expressed predominantly in the central nervous system during development.

Pathologic allelic variants. Weston et al [2004] identified four mutations in three families with Usher syndrome type 2C; all of the affected members in these families were female and none of the mutations involved isoform c. Several males with GPR98 mutations, including a large deletion in members of an Iranian family [Hilgert et al 2009], have now been reported [Ebermann et al 2009]; the total number of known mutations is currently about 50.

Normal gene product. The protein encoded by GPR98 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 GPR98 is very like that of cadherins, two of which are encoded by genes associated with Usher type I (CDH23 and PCDH15). There are three isoforms (a, b, c) of GPR98, all of which are expressed in fetal retina and cochlea. Isoform a is the smallest and least abundant; it has 1967 amino acids. The longest, isoform b, has 6306 amino acids with a predicted molecular weight of 692 kd; it is the largest known cell-surface receptor protein and is the predominant isoform in both the retina and the inner ear [Zou et al 2010]. Isoform c has 2296 amino acids [McMillan et al 2002]. The very large extracellular portion of GPR98 isoform b has 35 CalX-β modules, and the C-terminal residues correspond to the consensus motif for a PDZ-binding domain.

Abnormal protein product. See Molecular Genetic Pathogenesis.

Most of the GPR98 mutations reported in individuals with USH2 result in a truncated protein [Besnard et al 2012].

DFNB31

Normal allelic variants. DFNB31 contains 12 exons and spans 101 kb of genomic sequence.

Pathologic allelic variants. Ebermann et al [2007] identified a nonsense mutation in exon 1 and an exon 2 splice donor site mutation in affected members of a German family with USH2. However, no evidence of causal DFNB31 mutations was found in a study of 195 individuals with Usher syndrome, suggesting that the percentage of people with Usher syndrome type 2D is small [Aller et al 2010].

Normal gene product. Whirlin is a scaffold protein and has a similar structure to harmonin (the USH1C gene product) with up to three PDZ domains and a proline-rich domain. It has multiple isoforms, including the C-terminal isoform (<400 amino acids) and the long isoform (907 amino acids). Both of these isoforms are found in the cochlea, but only the long isoform is expressed in the retina.

Abnormal protein product. See Molecular Genetic Pathogenesis.

All mutations associated with Usher syndrome type 2D affect only the long isoform of whirlin. The whirlin knockout mouse has early-onset hearing loss and retinal degeneration starting at age 28 months, and its photoreceptors and hair cells show mislocalization and reduced expression of both usherin and GPR98. Returning whirlin to this mouse via gene therapy restores normal localization and expression levels of all three proteins [Yang et al 2010, Zou et al 2010].

References

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. Available online. 2002. Accessed 8-14-13.
  2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 8-14-13.

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Suggested Reading

  1. Cohen M, Bitner-Glindzicz M, Luxon L. The changing face of Usher syndrome: Clinical implications. Int J Audiol. 2007;46:82–93. [PubMed: 17365059]
  2. Fakin A, Jarc-Vidmar M, Glavac D, Bonnet C, Petit C, Hawlina M. Fundus autofluorescence and optical coherence tomography in relation to visual function in Usher syndrome type 1 and 2. Vision Res. 2012;75:60–70. [PubMed: 23000274]
  3. Malm E, Pojavic V, Moller C, Kimberling WJ, Andreasson S. Phenotypes in defined genotypes including siblings with Usher syndrome. Ophthalmic Genet. 2011;32:65–74. [PubMed: 21174530]
  4. Malm E, Ponjavic V, Möller C, Kimberling WJ, Stone ES, Andréasson S. Alteration of rod and cone function in children with Usher syndrome. Eur J Ophthalmol. 2011;21:30–38. [PubMed: 20544672]
  5. Yang J, Wang L, Song H, Sokolov M. Current understanding of Usher syndrome type II. Front Biosci. 2012;17:1165–83. [PMC free article: PMC3303697] [PubMed: 22201796]

Chapter Notes

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 August 2013 (me) Comprehensive update posted live
  • 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
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    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

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