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Nonsyndromic Hearing Loss and Deafness, DFNA3

, MD, , BA, and , PhD.

Author Information
, MD
Professor of Internal Medicine, Division of Nephrology
Sterba Hearing Research Professor of Otolaryngology
Director, Molecular Otolaryngology and Renal Research Laboratories
University of Iowa
Iowa City, Iowa
, BA
Molecular Otolaryngology and Renal Research Laboratories
University of Iowa
Iowa City, Iowa
, PhD
Department of Genetics
University of Antwerp
Antwerp, Belgium

Initial Posting: ; Last Update: June 12, 2014.

Summary

Disease characteristics. Nonsyndromic hearing loss and deafness, DFNA3, is characterized by pre- or postlingual, mild to profound, progressive high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings. Most individuals diagnosed as having DFNA3 have a deaf parent; the family history is rarely negative.

Diagnosis/testing. DFNA3 is caused by presence of a dominant-negative pathogenic variant in GJB2 or in GJB6 altering either the protein connexin 26 (Cx26) or connexin 30 (Cx30), respectively. Diagnosis depends on molecular genetic testing to identify a pathogenic variant in either gene.

Management. Treatment of manifestations: Fitting with hearing aids and appropriate educational programs. Cochlear implantation may be performed for persons with profound deafness.

Surveillance: Semiannual audiogram following initial diagnosis.

Agents/circumstances to avoid: Environmental exposures known to cause hearing loss, such as repeated loud noises.

Evaluation of relatives at risk: Molecular genetic testing for at-risk relatives of individuals with a known pathogenic variant; pure tone audiometry for at-risk family members when molecular genetic testing is not available.

Genetic counseling. DFNA3 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the altered gene. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Diagnosis

Diagnosis of nonsyndromic hearing loss and deafness, DFNA3 should be suspected in individuals with the following:

  • Pre- or postlingual, mild to profound, progressive sensorineural hearing impairment [Denoyelle et al 2002]

    Note: (1) Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 15 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90dB), or profound (>90dB). The frequency of hearing loss is designated as low (<500Hz), middle (501-2000Hz), or high (>2000Hz) (see Hereditary Hearing Loss and Deafness Overview).
  • No related systemic findings identified by medical history and physical examination
  • A family history of nonsyndromic hearing loss consistent with autosomal dominant inheritance

The diagnosis of nonsyndromic hearing loss and deafness, DFNA3 is established in a proband by detection of a pathogenic variant in GJB2 or GJB6. GJB2, which encodes connexin 26, and GJB6, which encodes connexin 30, are the only two genes in which pathogenic variants are known to cause deafness at the DFNA3 locus. (See Table 1). GJB2 is shared by an overlapping locus, DFNB1, which is associated with autosomal recessive nonsyndromic hearing loss. Variants in GJB2 may cause either autosomal dominant DFNA3-associated or autosomal recessive DFNB1-associated nonsyndromic hearing loss and deafness. The mode of inheritance is ultimately determined by how the variant impacts the expression and function of the connexin 26 protein.

The preferred genetic testing strategy is use of a multi-gene panel that includes GJB2 and GJB6 as well as a number of genes in which mutation causes disorders associated with hearing loss (described in Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time. Multi-gene panels have been developed to screen the coding exons of all genes implicated in nonsyndromic hearing loss.

An alternative genetic testing strategy is single gene testing:

  • The first step in the genetic diagnosis of DFNA3 is sequence analysis of GJB2 exon 2.
  • If no pathogenic variants are identified in GJB2, consider sequencing of GJB6, with the caveat that only two reported DFNA3-causing pathogenic variants of GBJ6 have been reported.
  • If no pathogenic variant is found, deletion/duplication analysis can be performed for both GJB2 and GJB6.

It is relevant to note that an entire multi-gene panel can often be completed for less expense than Sanger sequencing of a large gene. Multi-gene panels are also agnostic to the audioprofile and therefore do NOT require ‘expert knowledge’ to predict a likely genetic cause of hearing loss for Sanger sequencing.

See relevant Image ACMGACT.jpg and Image ACMGalg.jpg.

Table 1. Summary of Molecular Genetic Testing Used in Nonsyndromic Hearing Loss and Deafness, DFNA3

Gene 1 Proportion of DFNA3 Attributed to Mutation of This GeneTest Method
GJB2>90%Sequence analysis 2, 3 / mutation scanning 4
Targeted mutation analysis 5
Deletion/duplication analysis 6, 7
GJB6<10%Sequence analysis 2, 4, 8
Targeted mutation analysis 5
Deletion/duplication analysis 6, 7

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Sequence analysis of GJB2 identifies 100% of pathogenic variants, including p.Trp44Cys, p.Trp44Ser, p.Asp46Asn, p.Thr55Asn, p.Pro58Ala, p.Arg75Gln, p.Arg75Trp, p.Arg143Gln, p.Met163Leu, p.Asp179Asn, p.Arg184Gln, and p.Cys202Phe, the ten pathogenic variants reported to segregate in persons with DFNA3 [Denoyelle et al 1998, Morlé et al 2000, Hamelmann et al 2001, Janecke et al 2001, Löffler et al 2001, Marziano et al 2003, Primignani et al 2003, Feldmann et al 2005, Melchionda et al 2005, Piazza et al 2005, Primignani et al 2007, Matos et al 2008, Bazazzadegan et al 2011].

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 between laboratories depending on the specific protocol used.

5. Note: Pathogenic variants included in a panel may vary by laboratory.

6. Testing that identifies exonic or whole-gene deletions/duplications not 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.

7. No deletions or duplications involving GJB2 or GJB6 have been reported to cause DFNA3 nonsyndromic hearing loss and deafness.

8. Two pathogenic variants in GJB6, p.Thr5Met and p.Ala40Val, have been reported in one Italian family and one Taiwanese individual with DFNA3 [Grifa et al 1999, Yang et al 2007].

Clinical Description

Natural History

Nonsyndromic hearing loss and deafness, DFNA3, is characterized by progressive, mild-to-severe high-frequency sensorineural hearing impairment. Prelingual and postlingual onset of hearing loss is reported with DFNA3-associated pathogenic variants in GJB2 while DFNA3-associated pathogenic variants in GJB6 cause prelingual hearing loss [Weegerink 2013]. When the hearing loss is postlingual, patients with DFNA3-associated hearing loss may pass the newborn hearing screen. DFNA3 audioprofiles may vary significantly, even within a family. Individuals with DFNA3 have no other associated medical findings.

Tests of vestibular function and computed tomography of the temporal bones in persons with DFNA3 are normal [Denoyelle et al 2002].

GJB2. The twelve missense pathogenic variants of GJB2 (p.Trp44Cys, p.Trp44Ser, p.Asp46Asn, p.Thr55Asn, p.Pro58Ala, p.Arg75Gln, p.Arg75Trp, p.Arg143Gln, p.Met163Leu, p.Asp179Asn, p.Arg184Gln, and p.Cys202Phe) that cause deafness at the DFNA3 locus are associated with at least two different audioprofiles based on age of onset.

The majority of pathogenic variants cause prelingual hearing loss (p.Trp44Cys, p.Pro58Ala, p.Arg75Gln, p.Arg75Trp, p.Arg143Gln and p.Arg184Gln):

  • The p.Trp44Cys audioprofile is characterized by a bilaterally symmetric sensorineural loss that varies from mild to profound, beginning with high-frequency hearing loss and progressing to loss at all frequencies.
  • Hearing loss related to the p.Pro58Ala pathogenic variant is progressive, ranging from mild to severe.
  • The hearing loss associated with the p.Arg75Gln and p.Arg75Trp pathogenic variants is usually profound (average threshold for p.Arg75Gln is 105 dbHL).
  • Individuals with the p.Arg143Gln pathogenic variant show a progressive profound high-frequency hearing loss.
  • Audioprofiles for individuals with the c.551G>A (p.Arg184Gln) pathogenic variant are downsloping and consistent with severe-to-profound prelingual hearing loss [Janecke et al 2001, Löffler et al 2001, Tekin et al 2001, Denoyelle et al 2002, Feldmann et al 2005, Primignani et al 2007, Weegerink et al 2011].

In contrast, deafness related to the pathogenic variants resulting in the substitutions p.Thr55Asn, p.Asp179Asn, and p.Cys202Phe is postlingual:

  • Audioprofiles of individuals with the c.164C>A (p.Thr55Asn) pathogenic variant have a downsloping pattern and are consistent with a severe-to-profound postlingual hearing loss.
  • Age of onset for hearing loss in individuals with the p.Asp179Asn pathogenic variant ranges from the first to the third decade. The audioprofile shows a mild-to-moderate hearing loss, particularly at high frequencies.
  • Hearing loss in individuals with the p.Cys202Phe pathogenic variant is usually not detected until the second decade. Initially, the loss preferentially affects the high frequencies but progresses to affect the middle frequencies by middle age [Morlé et al 2000, Denoyelle et al 2002, Primignani et al 2003, Melchionda et al 2005].

Other:

  • Audioprofiles for individuals with the p.Trp44Ser pathogenic substitution are not available.
  • The p.Asp46Asn substitution shows intrafamilial variability in the audioprofiles with some individuals showing postlingual progressive hearing loss with onset in the first decade of life and some showing prelingual hearing loss.
  • The p.Met163Leu pathogenic variant causes a mild-to-moderate high-frequency hearing loss; age of onset was not reported [Hamelmann et al 2001, Marziano et al 2003, Matos et al 2008, Bazazzadegan et al 2011].

GJB6. The p.Thr5Met pathogenic variant in GJB6 has been reported in one family [Grifa et al 1999]. The audioprofile of this family is characterized by middle- to high-frequency hearing loss. The degree of hearing loss is progressive and variable, ranging from mild to profound. The age of onset of hearing loss was not reported.

The p.Ala40Val substitution in GJB6 has been identified in one individual with autosomal dominant nonsyndromic hearing loss; the audioprofile and age of onset were not reported [Yang et al 2007, Wang et al 2011].

Genotype-Phenotype Correlations

See Natural History.

Penetrance

Causative mutations in GJB2 and GJB6 are fully penetrant. Individuals who inherit a dominant mutation in GJB2 or GJB6 develop DFNA3-associated nonsyndromic hearing loss. Recessive mutations in GJB2 or GJB6 cause DFNB1-associated nonsyndromic hearing loss.

Nomenclature

The different gene loci for nonsyndromic deafness are designated DFN (for DeaFNess).

Loci are named based on mode of inheritance:

The number following the above designations reflects the order of gene mapping and/or discovery.

Prevalence

The relative prevalence of DFNA3 as a cause of autosomal dominant nonsyndromic hearing loss is not known, but it is extremely rare. Fourteen pathogenic variants have been described worldwide. The majority of these pathogenic variants are described only in single families or simplex cases (i.e., a single occurrence in a family) [Denoyelle et al 2002, Hilgert et al 2009].

Prevalence for different pathogenic variants varies by population [Abe et al 2000, Hamelmann et al 2001, Löffler et al 2001, Liu et al 2002, Xiao & Xie 2004].

Differential Diagnosis

Other causes of postlingual, acquired forms of hearing loss need to be considered (see Deafness and Hereditary Hearing Loss Overview).

Autosomal dominant syndromic forms of hearing loss with:

  • Malformations of the head and neck. Branchiootorenal (BOR) syndrome is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment; branchial fistulae and cysts; and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis [Chang et al 2004]. Pathogenic variants in EYA1 are causative.
  • Pigmentary anomalies. Waardenburg syndrome type 1 (WS1) is characterized by congenital sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum (lateral displacement of the inner canthi) [DeStefano et al 1998].

    Hearing loss occurs in approximately 57% and is congenital, sensorineural, typically non-progressive, and either unilateral or bilateral. Most commonly, hearing loss is bilateral and profound (>100 dB). The majority of individuals with WS1 have either a white forelock (45%) or graying of the scalp hair before age 30 years. Affected individuals may have complete heterochromia iridium, partial/segmental heterochromia, or hypoplastic or brilliant blue irides. The diagnosis is established by clinical findings. Diagnostic criteria rely on the presence of sensorineural hearing loss, pigmentary changes, and calculation of the W index to identify dystopia canthorum. Pathogenic variants in PAX3 are causative.

See Deafness, Autosomal Dominant: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to autosomal dominant nonsyndromic deafness (DFNA), 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

Recommended following diagnosis of nonsyndromic hearing loss and deafness, DFNA3:

  • Complete assessment of auditory acuity using age-appropriate tests including ABR testing, auditory steady-state response (ASSR) testing, and/or pure tone audiometry
  • Medical genetics consultation

Treatment of Manifestations

The following treatment is indicated:

  • Fitting with appropriate hearing aids
  • Enrollment in an appropriate educational program for the hearing impaired
  • Consideration of cochlear implantation, a promising habilitation option for persons with profound deafness [Connell et al 2007]
  • Recognition that unlike with many clinical conditions, management and treatment of mild-to-profound deafness fall largely within the purview of the social welfare and educational systems rather than the medical care system [Smith et al 2005]

Prevention of Secondary Complications

Early diagnosis, habilitation with hearing aids or cochlear implantation, and educational programming will diminish the likelihood of long-term speech or educational delay.

Surveillance

The following are appropriate:

  • Semiannual examination by a physician who is familiar with hereditary hearing impairment
  • Repeat audiometry to confirm stability of hearing loss

Agents/Circumstances to Avoid

Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important is avoidance of repeated exposure to loud noises.

Evaluation of Relatives at Risk

Molecular genetic testing is recommended for at-risk relatives of individuals with a known pathogenic variant. Individuals with known pathogenic variants should be followed semiannually by a physician who is familiar with hereditary hearing impairment.

Recommendations for the evaluation of at-risk family members when molecular genetic testing is unavailable include pure tone audiometry to assess auditory acuity and review of medical history and physical examination to rule out other systemic findings.

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 human trials for this condition.

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

Nonsyndromic hearing loss and deafness, DFNA3, is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed as having DFNA3 have a deaf parent; the family history is rarely negative.
  • A proband with DFNA3 may have the condition as the result of de novo GJB2 or GJB6 mutation. The proportion of cases caused by de novo mutation is very small.
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include (a) assessment of auditory acuity using ABR emission testing and pure tone audiometry and (b) medical history and physical examination to determine if other systemic findings are present.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the proband's parents.
  • If one of the proband's parents has a GJB2 or GJB6 pathogenic variant, each sib has a 50% chance of inheriting the mutant allele.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If a pathogenic variant cannot be detected in the DNA extracted from leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Offspring of an affected individual have a 50% chance of inheriting the GJB2 or GJB6 pathogenic variant.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is deaf, his or her family members are at risk.

Related Genetic Counseling Issues

Establishing in infancy or early childhood whether a child at risk has inherited the altered GJB2 or GJB6 allele should be considered so that appropriate and early support and management can be provided to the child and the family. Molecular genetic testing for a GJB2 or GJB6 pathogenic variant can only be considered if a pathogenic variant in either gene has been identified in an affected family member.

Additional points to consider are the following:

  • Communication with individuals who are deaf requires the services of a skilled interpreter.
  • Deaf persons may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." In fact, having a deaf child may be preferred over having a child with normal hearing.
  • Many deaf people are interested in obtaining information about the cause of their own deafness including information on medical, educational, and social services rather than information about prevention, reproduction, or family planning. As in all genetic counseling, it is important for the counselor to identify, acknowledge, and respect the individual's/family's questions, concerns, and fears.
  • The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "affected," "abnormal," and "disease causing" should be avoided.

Family planning

  • The optimal time for determination of genetic risk 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 deaf.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the condition, the GJB2 or GJB6 mutation is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the GJB2 or GJB6 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions like DFNA3 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 GJB2 or GJB6 pathogenic variant has 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.

  • 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
  • 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

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. Nonsyndromic Hearing Loss and Deafness, DFNA3: 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 Nonsyndromic Hearing Loss and Deafness, DFNA3 (View All in OMIM)

121011GAP JUNCTION PROTEIN, BETA-2; GJB2
601544DEAFNESS, AUTOSOMAL DOMINANT 3A; DFNA3A
604418GAP JUNCTION PROTEIN, BETA-6; GJB6
612643DEAFNESS, AUTOSOMAL DOMINANT 3B; DFNA3B

GJB2

Gene structure. Most connexin genes have a common architecture, with the entire coding region contained in a single large exon separated from the 5'-untranslated region by an intron of variable size. The coding sequence of GJB2 (exon 2) is 681 base pairs (including the stop codon) and is translated into a 226-amino acid protein, connexin 26 (Cx26). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Numerous benign alleles of GJB2 have been reported and are listed on the Connexin-Deafness Home Page.

Pathogenic allelic variants. There are 12 known pathogenic variants in GJB2 (see Table 2). The majority of these pathogenic variants have been shown to segregate in families; however, the p.Arg75Gln and p.Arg75Trp pathogenic variants of GJB2 have also been identified as de novo mutations in simplex cases (i.e., a single occurrence in a family). These two pathogenic variants are implicated in both autosomal dominant nonsyndromic hearing loss and syndromic hearing loss associated with skin disorders (see Genetically Related (Allelic) Disorders [Janecke et al 2001, Feldmann et al 2005].

The pathogenicity of the p.Arg75Trp variant has been questioned as it has been reported in one of 77 Egyptian controls whose hearing status was not reported [Richard et al 1998]. However, subsequent case reports, animal models, and functional studies strongly argue for the pathogenicity of this variant [Janecke et al 2001, Kudo et al 2003, Maeda et al 2005, Maeda et al 2009, Mani et al 2009, Yum et al 2010, Weegerink et al 2011, Zhang et al 2011].

Table 2. Selected GJB2 Allelic Variants

Variant ClassificationDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
Benignc.101T>Cp.Met34Thr 1NM_004004​.5
NP_003995​.2
Pathogenicc.132G>Cp.Trp44Cys
c.136G>Ap.Asp46Asn
c.164C>Ap.Thr55Asn
c.131G>Cp.Trp44Ser
c.172C>Gp.Pro58Ala
c.223C>Tp.Arg75Trp
c.224G>Ap.Arg75Gln
c.428G>Ap.Arg143Gln
c.487A>Cp.Met163Leu
c.535G>Ap.Asp179Asn
c.551G>Ap.Arg184Gln
c.605G>Tp.Cys202Phe

Note on variant classification: Variants listed in the table have been provided by the authors. 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 found in normal hearing persons and family with palmoplantar keratoderma

Normal gene product. Connexin 26 is a beta-2 gap junction protein. Gap junctions are highly specialized organelles consisting of clustered channels that permit direct intercellular exchange of ions and molecules through central aqueous pores. Postulated roles include the rapid propagation of electrical signals and synchronization of activity in excitable tissues and the exchange of metabolites and signal molecules in non-excitable tissues [Evans & Martin 2002].

Each connexin protein contains two extracellular (E1-E2), four transmembrane (M1-M4), and three cytoplasmic domains (N-terminus, C-terminus, and a cytoplasmic loop located between M2 and M3) [Maeda et al 2009]. Each extracellular domain contains three cysteine residues joined between the E1 and E2 loops by at least one disulfide bond [Kovacs et al 2007, Yeager & Harris 2007]. The presumed importance of these six cysteines can be inferred from Cx32 experiments in which any Cys mutation completely blocks the development of gap-junction conductances between Xenopus oocyte pairs. The third transmembrane domain (M3) is amphipathic and lines the putative wall of the intercellular channel [Kovacs et al 2007, Yeager & Harris 2007], which is created by oligomerization of six connexins to form a hexameric structure called a connexon. Two connexons, one from each cell, join in the extracellular gap to complete the cell-to-cell pathway. If the connexons contributed by each cell are of identical composition, the channel is homotypic; if each connexon is formed by a different composition of connexins, it is termed heterotypic. Most connexins are phosphoproteins and undergo post-transcriptional modifications [Moreno 2005, Locke et al 2006]. Cx26 forms functional combinations with itself, Cx30, Cx31, Cx32, Cx46, and Cx50 [Cottrell & Burt 2005, Liu et al 2009].

Abnormal gene product. Gap junction channels are permeable to ions and small metabolites with relative molecular masses up to approximately 1.2 kd [Harris & Bevans 2001]. Differences in ionic selectivity and gating mechanisms among gap junctions reflect the existence of over 20 different connexin isoforms in humans.

The abnormal gene product in DFNA3 causes deafness via a dominant-negative mechanism of action. The majority of the pathogenic variants in GJB2 have been functionally tested for dominant-negative effects in recombinant expression systems (p.Trp44Cys, p.Trp44Ser, p.Arg75Trp, p.Arg75Gln, p.Arg143Gln, p.Met163Leu, p.Asp179Asn, p.Arg184Gln and p.Cys202Phe). The ability to prevent formation of functional gap junction channels was first demonstrated with the p.Arg75Trp pathogenic variant in a Xenopus oocyte model system [Richard et al 1998, Mani et al 2009]. The p.Trp44Cys, p.Trp44Ser, and p.Arg75Gln pathogenic variants have been shown to prevent functional channel formation in vitro [Bruzzone et al 2001, Marziano et al 2003, Piazza et al 2005]. In addition to dominant-negative inhibition of wild-type Cx26, most of the pathogenic variants (p.Trp44Cys, p.Trp44Ser, p.Arg75Trp, p.Arg75Gln, p.Arg143Gln, p.Asp179Asn, p.Arg184Gln, and p.Cys202Phe) also show a trans-dominant-negative effect on wild-type Cx30 channel formation. The p.Met163Leu pathogenic variant shows a dominant-negative effect on appropriate protein trafficking and cell viability [Matos et al 2008]. The Thr55Asn variant displays impaired trafficking and fails to reach the plasma membrane [Melchionda et al 2005].

GJB6

Gene structure. The majority of gap junction genes have two exons; a few have only one exon, and one, GJB6, has three exons, of which only the third is coding. The translated protein, connexin 30 (Cx30), is 261 amino acids long. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. There are only two known DFNA3-causing pathogenic variants of GBJ6: p.Thr5Met and p.Ala40Val [Grifa et al 1999, Yang et al 2007] (see Table 3).

Table 3. Selected GJB6 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.14C>Tp.Thr5Met 1NM_001110219​.2
NP_001103689​.1
c.119C>Tp.Ala40Val

Note on variant classification: Variants listed in the table have been provided by the authors. 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. See also Table 1 and Natural History, GJB6.

Normal gene product. Connexin 30 is a beta-6 gap junction protein. It shares an architecture that is common to all connexins (see GJB2, Normal gene product).

Abnormal gene product. Like the abnormal gene products of GJB2 in DFNA3, the p.Thr5Met and p.Ala40Val variants of GJB6 act via a dominant-negative mechanism to inhibit activity of wild-type Cx30 gap junction channels. Additionally, the p.Ala40Val variant exerts a trans-dominant-negative effect on Cx26, impairing gap junction formation in the cochlea. In functional studies with a mouse model, the p.Thr5Met variant was shown to exert its pathogenic effect through diminished biochemical coupling between cochlear cells [Grifa et al 1999, Schütz et al 2010, Wang et al 2011].

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 6-4-14.
  2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 6-4-14.

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Suggested Reading

  1. Nickel R, Forge A. Gap junctions and connexins in the inner ear: their roles in homeostasis and deafness. Curr Opin Otolaryngol Head Neck Surg. 2008;16:452–7. [PubMed: 18797288]
  2. Zhao HB, Kikuchi T, Ngezahayo A, White TW. Gap junctions and cochlear homeostasis. J Membr Biol. 2006;209:177–86. [PMC free article: PMC1609193] [PubMed: 16773501]

Chapter Notes

Acknowledgments

This work was originally supported in part by research grants 1RO1 DC02842 (RJHS), HG00457 (VCS), P50HG00835 (VCS), and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC).

Author History

Paul T Ranum, BA (2014-present)
Daryl A Scott, MD, PhD; University of Iowa (1998-2001)
Abraham M Sheffield, MD; University of Iowa (2009-2014)
Val C Sheffield, MD, PhD; University of Iowa (1998-2001)
Richard JH Smith, MD (1998-present)
Guy Van Camp, PhD (1998-present)

Revision History

  • 12 June 2014 (me) Comprehensive update posted live
  • 19 April 2012 (me) Comprehensive update posted live
  • 30 April 2009 (me) Comprehensive update posted live
  • 29 December 2005 (me) Comprehensive update posted to live Web site
  • 15 July 2004 (rjs) Revision: use of an interpreter
  • 27 October 2003 (me) Comprehensive update posted to live Web site
  • 24 April 2001 (me) Comprehensive update posted to live Web site
  • 28 September 1998 (pb) Review posted to live Web site
  • 4 April 1998 (rjs) Original submission
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