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Usher Syndrome Type I

Synonym: USH1. Includes: USH1B, USH1C, USH1D, USH1E, USH1F, USH1G, USH1H, USH1J, USH1K

, 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: June 20, 2013.

Summary

Disease characteristics. Usher syndrome type I is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. Unless fitted with a cochlear implant, individuals do not typically develop speech. Retinitis pigmentosa (RP), a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.

Diagnosis/testing. The diagnosis of Usher syndrome type I is established on clinical grounds using electrophysiologic and subjective tests of hearing and retinal function. Mutations in genes at a minimum of nine different loci cause Usher syndrome type I. Genes at six of these loci – MYO7A (USH1B), USH1C, CDH23 (USH1D), PCDH15 (USH1F), USH1G, and CIB2 (USH1J) – have been identified.

Management. Treatment of manifestations: Hearing aids are usually ineffectual; cochlear implantation should be considered, especially for young children. Communication skills may be optimized if all family members (i.e., in addition to affected children) receive specialized training from educators of the hearing impaired. Progressive vision loss may eventually limit communication to tactile signing.

Surveillance: Routine ophthalmologic evaluation to detect potentially treatable complications such as cataracts.

Agents/circumstances to avoid: Competition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous; progressive loss of peripheral vision impairs the ability to safely drive a car. Because of the high risk for disorientation when submerged in water, swimming needs to be undertaken with caution.

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 I is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who has had a child with Usher syndrome type I 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 for pregnancies at increased risk for most forms of Usher syndrome type I is possible if the disease-causing mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

A diagnosis of Usher syndrome type I requires the following:

Molecular Genetic Testing

Genes. Six genes in which mutations are known to cause Usher syndrome type I have been identified. Subtypes of Usher syndrome type I and associated genes:

  • USH1B: MYO7A
  • USH1C: USH1C
  • USH1D: CDH23
  • USH1F: PCDH15
  • USH1G: USH1G
  • USH1J: CIB2

Evidence for locus heterogeneity

  • A seventh locus associated with Usher syndrome type I (USH1E) has been mapped to 21q21; the gene is not yet known.
  • An eighth locus associated with Usher syndrome type I (USH1H) has been mapped to 15q22-q23 [Ahmed et al 2009].
  • A ninth locus associated with Usher syndrome type I (USH1K) has been mapped to 10p11.21-q21.1 [Jaworek et al 2012].
  • 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).

Testing

Table 1. Summary of Molecular Genetic Testing Used in Usher Syndrome Type I (USH1)

Gene 1
(Locus Name)
Proportion of USH1 Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
MYO7A
(USH1B)
53%-63%Sequence analysisSequence variants 1, 4, 5, 6
Targeted mutation analysisPanel of targeted known sequence variants 7
Deletion/duplication analysis 8Exonic or whole-gene deletions
USH1C
(USH1C)
1%-15% 9Sequence analysisSequence variants 4
Targeted mutation analysisPanel of targeted known sequence variants 7
Deletion/duplication analysis 8Exonic or whole-gene deletions 10
CDH23
(USH1D)
7%-20%Sequence analysisSequence variants 1,4, 6
Targeted mutation analysisPanel of targeted known sequence variants 7
Deletion/duplication analysis 8Exonic or whole-gene deletions
Unknown
(USH1E)
RareLinkage analysis 11N/A
PCDH15
(USH1F)
7%-12%Sequence analysisSequence variants 4
Targeted mutation analysisp.Arg245* 12
Deletion/duplication analysis 8Exonic or whole-gene deletions 13
USH1G
(USH1G)
Rare (0%-4%)Sequence analysisSequence variants 4
Targeted mutation analysisPanel of targeted known sequence variants 7
Deletion/duplication analysis 8Unknown, none reported 14
Unknown
(USH1H)
RareLinkage analysis 11N/A
CIB2 (USH1J)UnknownSequence analysisSequence variants 4
Deletion/duplication analysis 8Unknown, none reported 14
Unknown
(USH1K)
UnknownLinkage analysis 11N/A

N/A = not applicable

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

2. Bonnet et al [2011], Roux et al [2011], Stabej et al [2012]

3. See Molecular Genetics for information on allelic variants.

4. 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.

5. Maubaret et al [2005], Jaijo et al [2007]

6. Detects ~90% of mutations in MYO7A or CDH23

7. Mutations in testing panels and mutation detection frequency may vary by laboratory.

8. 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.

9. Almost all Usher syndrome type I in the Acadian population is USH1C.

10. Rare exonic or multiexonic deletions have been reported [Bitner-Glindzicz et al 2000].

11. Linkage analysis may be possible for families in which USH1E, USH1H, or USH1K is segregating.

12. The p.Arg245* (c.733C>T) mutation is detected in a large percentage of Ashkenazi Jewish individuals with USH1F.

13. Deletions/duplications account for 37% of PCDH15 mutations [Roux et al 2011].

14. No deletions or duplications involving USH1G or CIB2 have been reported to cause Usher syndrome. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Test characteristics. Information on test sensitivity and specificity and other test characteristics can be found at www.eurogentest.org [Bolz & Roux 2011 (click here for full text)].

Testing Strategy

To confirm/establish 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 USH1C or PCDH15, respectively (see Table 1, footnotes 9 and 12).
  • If the individual does not have these ancestries or mutations are not found in these two genes, either single-gene testing or multi-gene panels are performed.
    • Single-gene testing. One strategy for molecular diagnosis of a proband suspected of having Usher syndrome type I is sequencing each gene individually (sequencing of MYO7A, CDH23, PCDH15, USH1C, USH1G, and CIB2 followed by deletion/duplication analyses).
    • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having Usher syndrome type I is use of a multi-gene panel.

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 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 Correlations

CDH23. 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 I, atypical Usher type I, and DFNB18, respectively [Astuto et al 2002].

Penetrance

Penetrance is complete in Usher syndrome type I.

Anticipation

Anticipation has not been reported in Usher syndrome type I.

Nomenclature

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).

Prevalence

In older publications the prevalence of Usher syndrome has been reported to range from 3.2 to 6.2 per 100,000. Usher syndrome was estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. Many of these estimates were made prior to 1989, when Moller et al [1989] subdivided Usher syndrome into Usher syndromes type I and II, and before the recognition of Usher syndrome type III. The specialized educational requirements of the congenitally deaf have historically rendered the population with Usher syndrome type I more accessible for study by researchers. Persons with Usher syndrome type II or Usher syndrome type III, who communicate orally and who are mainstreamed into regular schools, are not well represented in these estimates. It has been argued that the prevalence of Usher syndrome in the general population may therefore be substantially greater.

A recent 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 one in 6,000 [Kimberling et al 2010].

Differential Diagnosis

Nonsyndromic 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 [Fakin et al 2012]. 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 CLRN1 or HARS are causative [Joensuu et al 2001, Vastinsalo et al 2011, Puffenberger et al 2012]. 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.

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 I, the following evaluations are recommended:

  • Audiology. Otoscopy, pure tone 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 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.

Surveillance

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

Agents/Circumstances to Avoid

Competition 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 Risk

It 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 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

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

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].

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 I is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The unaffected parents of an individual with Usher syndrome type I are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation in a gene associated with Usher syndrome type I.
  • Heterozygotes (carriers) 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 unaffected 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.

Offspring of a proband

  • The unaffected offspring of an affected individual are obligate heterozygotes. If the other parent is a carrier of a mutation in the same Usher-related gene, each offspring has a 50% chance of being affected. If the other parent has the same genetic type of Usher syndrome, all offspring will be affected.
  • Assuming that (1) the prevalence of Usher syndrome is one in 20,000, (2) 25% of individuals with Usher syndrome have type I, and (3) 50% of individuals with Usher syndrome type I have type IB, the population carrier frequency is approximately one in 200 for type IB. Thus, for each pregnancy of a couple in which one partner has Usher syndrome type I and the other partner has normal hearing and no family history of Usher syndrome, the probability of a child having Usher syndrome type IB is one in 800. When similar calculations are done for the other forms of USH1, the total probability of this couple having a child with Usher syndrome type I is approximately one in 500. (Note that this probability would not be correct if both parents are of Acadian or Ashkenazi Jewish ancestry.)

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 for at-risk family members 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 for most types of Usher syndrome type 1 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 I: 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 I (View All in OMIM)

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; USH1K

Molecular Genetic Pathogenesis

The six known USH1 proteins interact with one another, with the PDZ domains of harmonin playing a central role in this network. If any one of the molecules in this "Usher 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, Riazuddin et al 2012].

Note: A comprehensive set of databases (UMD-USHbases) provides information about mutations responsible for Usher syndrome [Baux et al 2008].

MYO7A

Normal allelic variants. MYO7A contains 49 exons and spans a genomic region of approximately 87 kb. There are seven different transcripts, the longest being 7.4 kb.

Pathologic allelic variants. Over 200 mutations have been reported in MYO7A, most of them associated with Usher syndrome type IB. They are located throughout the gene, although many are clustered in the exons that encode conserved domains of the protein [Bonnet et al 2011, Roux et al 2011, Stabej et al 2012].

Normal gene product. The myosin VIIa 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. Mutations in mouse myo7a were found in shaker-1 (sh1) mice; sh1 mice are deaf and have vestibular areflexia but no RP, although they do have mild ERG abnormalities [Libby & Steel 2001].

Detailed molecular genetic and histologic examination of sh1 mice has helped to illuminate the role that myosin VIIa 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 VIIa is believed to be attached to the actin-rich network within the hair cell bundle. Myosin VIIa colocalizes with crosslinks that connect the shafts of stereocilia, suggesting that it is required for structural organization of the hair cell bundles. Electron microscopy indicates that myosin VIIa 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 VIIa 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]. Liu et al [1998b] demonstrated with electron microscopy that mutant myosin VIIa 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). 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]. The inner and outer segments of rod photoreceptors are joined by the connecting cilium and both opsin and myosin VIIa 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 VIIa and opsin, suggesting that the actin cytoskeleton of the cilium may provide the structural bases for myosin VIIa-linked trafficking of membrane components, including rhodopsin, from the inner to the outer segments [Wolfrum & Schmitt 2000].

Abnormal gene product. See Molecular Genetic Pathogenesis.

Although the majority of MYO7A mutations associated with Usher syndrome type IB are expected to result in a prematurely truncated non-functional protein (frameshift, nonsense, splice site), a relatively high percentage (37%) are missense mutations [Roux et al 2011].

USH1C

Normal allelic variants. USH1C has 28 exons spanning 51 kb of genomic sequence 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]. 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 mutation c.216G>A (see Table 2) [Savas et al 2002].

Pathologic allelic variants. See Table 2. The first USH1C mutations identified include the Acadian founder mutation c.216G>A, which was shown to create a cryptic splice donor in exon 3 affecting mRNA stability and usage of the normal exon 3 splice donor [Bitner-Glindzicz et al 2000, Lentz et al 2005].

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 I phenotype ranges from 1.65% to 12.5% [Blaydon et al 2003, Ouyang et al 2003].

More than 20 mutations have now been reported, with most of them either located in an exon encoding a PDZ domain of the protein or affecting splicing [Bonnet et al 2011, Roux et al 2011, Stabej et al 2012]. A study of Usher syndrome type I patients in Spain identified two new mutations, one nonsense and one frameshift, and estimated that USH1C mutations are responsible for 1.5% of Usher syndrome type I in the Spanish population [Aparisi et al 2010].

Table 2. USH1C Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
Normalc.496+59_496+103[9]No impact on proteinNM_005709​.3
NP_005700​.2
Pathologicc.216G>A 1p.Val72Glufs*65
c.238dupCp.Arg80Profs*69

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. G to A change in exon 3 created a new splice site, resulting in a 35-bp deletion in 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 tips 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 VIIa 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.

CDH23

Normal allelic variants. CDH23 has 70 exons and spans more than 400 kb of genomic sequence. Over 80 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 and differ by the inclusion or exclusion of the 105-nucleotide exon 68 [Bork et al 2001, Di Palma et al 2001]. 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. At least 150 mutations have been reported in CDH23 [Bonnet et al 2011, Roux et al 2011, Stabej et al 2012]. Most of the mutations associated with Usher syndrome type ID are null (nonsense, frameshift, splice site) and result in a more severe phenotype than missense mutations. A large deletion resulting in the loss of three exons was reported in a Japanese patient [Nakanishi et al 2010].

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 3354 amino acids and 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]. 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.

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].

Compound heterozygotes for one USH1D allele and one DFNB12 allele are deaf, but vision and balance are preserved; they do not have Usher syndrome type ID [Schultz et al 2011].

PCDH15

Normal allelic variants. PCDH15 has 33 exons, with the start codon residing in the second exon; it spans close to a megabase of genomic sequence. PCDH15 was implicated as the USH1F-associated gene by the observation of orthologous mouse mutations in the Ames waltzer deafness mouse [Alagramam et al 2001a].

Pathologic allelic variants. See Table 3. At least 50 different mutations have been reported [Bonnet et al 2011, Roux et al 2011, Stabej et al 2012]. Many of the point mutations are private and null; no mutational hotspots have been identified [Jaijo et al 2012]. Large deletions and duplications within PCDH15 are a significant cause of USH1F [Le Guédard et al 2007, Aller et al 2010].

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. PCDH15 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.733C>Tp.Arg245*NM_033056​.3
NP_149045​.3

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.

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; it has 1955 amino acids, 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.

USH1G

Normal allelic variants. USH1G comprises three exons, but the third exon includes only the TAA stop codon. It spans 7.2 kb of genomic sequence.

Pathologic allelic variants. See Table 4. At least ten mutations have been reported [Bonnet et al 2011, Roux et al 2011, Stabej et al 2012]. A 20-nucleotide homozygous deletion (p.Ser278Profs*71) was found in the original consanguineous Palestinian family that defined the linkage of USH1G to chromosome 17q [Mustapha et al 2002]. A second homozygous mutation (p.Val132Glyfs*3), found in a large consanguineous Tunisian family, was 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]. Recently a homozygous mutation (p.Ser243*) was found in cochlear-implanted Saudi siblings with some atypical retinal findings [Imtiaz et al 2012].

Table 4. USH1G Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
c.394dupG
(c.393insG)
p.Val132Glyfs*3NM_033056​.3
NP_149045​.3
c.832_851del
(c.828-849del20)
p.Ser278Profs*71NM_173477​.2
NP_775748​.2

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. Variant designation that does not conform to current naming conventions

Normal 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 co-transfection experiments, the PDZ1 domain of harmonin interacted with the PBI carboxy-terminus of Sans, suggesting that Sans is another macromolecular component of the Usher interactome, and 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.

The retinal phenotype is quite variable among patients with Usher syndrome type IG, perhaps due in part to the location of the mutation and its effect on the encoded protein.

CIB2

Normal allelic variants. CIB2 has six exons spanning 26 kb of genomic sequence; it encodes three alternatively spliced isoforms.

Pathologic allelic variants. A single base pair mutation (c.192G>C) was found in a homozygous state in affected individuals from a large consanguineous Pakistani family [Riazuddin et al 2012].

Table 3. CIB2 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.192G>Cp.Glu64AspNM_006383​.3
NP_006374​.1

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.

Normal gene product. CIB2 encodes a calcium- and integrin-binding protein with the largest isoform consisting of 210 amino acids. It contains three or four EF-hand domains that change conformation upon binding calcium and are hypothesized to mediate intracellular calcium signaling. CIB2 mRNA expression has been detected in both human and mouse tissues including the inner ear and retina. In the mouse ear, developmental CIB2 expression has been localized to supporting cells of the organ of Corti and vestibular epithelia and adult expression has been localized to the stereocilia of the organ of Corti and vestibular hair cells. CIB2 has been shown to interact with Usher proteins whirlin and myosin VIIa; thus, it is a member of the Usher interactome [Riazzudin et al 2012].

Abnormal gene product. See Molecular Genetic Pathogenesis.

The c.192G>C (p.Glu64Asp) mutation affects all three isoforms of CIB2. Riazzudin et al [2012] suggest that this Glu64 substitution may weaken the interaction of CIB2 with integrin, which would affect integrin activation and perhaps also calcium binding.

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. (pdf) Available online. 2002. Accessed 6-17-13.
  2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 6-17-13.

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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]
  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. Goldmann T, Overlack N, Moller F, Belakhov V, van Wyk M, Baasov T, Wolfrum U, Nagel-Wolfrum K. A comparative evaluation of HB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. EMBO Mol Med. 2012;4:1186–99. [PMC free article: PMC3494875] [PubMed: 23027640]
  4. Jacobsen SG, Cideciyan AV, Gibbs D, Sumaroka A, Roman AJ. et al. Retinal disease course in Usher syndrome 1B due to MYO7A mutations. Invest Ophthalmol Vis Sci. 2011;52:7924–36. [PMC free article: PMC3263772] [PubMed: 21873662]
  5. Lentz JJ, Jodelka FM, Hinrich AJ, McCaffrey KE, Farris HE. et al. Rescue of hearing and vestibular function by antisense olgonucleotides in a mouse model of human deafness. Nat Med. 2013;19:345–50. [PMC free article: PMC3657744] [PubMed: 23380860]
  6. 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]
  7. 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;21:30–8. [PubMed: 20544672]
  8. Overlack N, Goldmann T, Wolfrum U, Nagel-Wolfrum K. Gene repair of an Usher syndrome causing mutation by zinc-finger nuclease mediated homologous recombination. Invest Ophthalmol Vis Sci. 2012;53:4140–6. [PubMed: 22661463]
  9. Pan L, Zhang M. Structure of Usher Syndrome 1 proteins and their complexes. Physiology. 2012;27:25–42. [PubMed: 22311968]
  10. Sahly I, Dufour E, Schietroma C, Michel V, Bahloul A. et al. Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice. J Cell Biol. 2011;199:381–99. [PMC free article: PMC3471240] [PubMed: 23045546]
  11. Williams DS, Lopes VS. Gene therapy strategies for Usher syndrome type IB. Adv Exp Med Biol. 2012;723:235–42. [PubMed: 22183338]

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)
Sandra Pieke-Dahl, PhD; Ohio State University (1999-2006)
Michael D Weston, MA; Boys Town National Research Hospital (1999-2006)

Revision History

  • 20 June 2013 (me) Comprehensive update posted live
  • 28 October 2010 (me) Comprehensive update posted live
  • 29 June 2010 (cd) Revision: sequence analysis and prenatal testing available for USH1G; USHIH locus added
  • 28 May 2009 (me) Comprehensive update posted live
  • 14 May 2008 (cd) Revision: prenatal testing available for CDH23
  • 10 December 2007 (cd) Revision: sequence analysis of exon 3 of USH1C available clinically
  • 5 November 2007 (cd) Revision: sequence analysis of the entire coding regions of PCDH15 (USH1F) and CDH23 (USH1D) available clinically
  • 7 November 2006 (me) Comprehensive update posted to live Web site
  • 6 February 2004 (cd) Revision: change in gene name (SANS to USH1G)
  • 13 January 2004 (wk) Author revisions
  • 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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