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Nonsyndromic Hearing Loss and Deafness, DFNA3

Summary

Disease characteristics. DFNA3 is characterized by childhood-onset, progressive, moderate-to-severe high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings.

Diagnosis/testing.  DFNA3 is caused by presence of a mutation in the GJB2 gene or in the GJB6 gene altering either the protein connexin 26 (Cx26) or connexin 30 (Cx30), respectively. Diagnosis depends upon molecular genetic testing to identify a deafness-causing mutation in either gene. Such testing is available on a clinical basis and detects 100% of the deafness-causing mutations.

Management.  Management of DFNA3 includes fitting with hearing aids and appropriate educational programs. Cochlear implantation may be performed for persons with profound deafness. Surveillance includes semi-annual audiograms.

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 is available on a clinical basis.

Diagnosis

Clinical Diagnosis

DFNA3 is suspected in individuals with the following:

• Pre- or post-lingual, 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

Molecular Genetic Testing

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

Gene.   GJB2, which encodes connexin 26, and GJB6, which encodes connexin 30, are the only two genes known to be associated with deafness at the DFNA3 locus.

Molecular genetic testing: Clinical uses

• Diagnostic testing
• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• GJB2 sequence analysis.  Sequence analysis of GJB2 identifies 100% of mutations, including W44C, R75Q, R75W, and C202F, the four mutations reported to segregate in persons with DFNA3 [Denoyelle et al 1998 , Feldmann et al 2005 , Morle et al 2000].

• GJB6 sequence analysis.  A mutation in the GJB6 gene, T5M, has been reported in one family with DFNA3 [Grifa et al 1999].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in DFNA3 Test Method Mutations Detected Mutation Detection Rate Test Availability Sequence analysis W44C, R75Q, R75W, and C202F in GJB2 100%  1 Clinical T5M in GJB6 100%  2 Clinical

1. Fewer than 0.05% of families screened for GJB2 deafness-causing allelic variants 2. Reported in a single Italian family by Grifa et al 1999

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

Genetically Related (Allelic) Disorders

Other phenotypes have been associated with mutations in GJB2 and GJB6:

GJB2

• DFNB1 , an autosomal recessive (or possibly digenic) disorder of (generally), moderate-to-severe sensorineural impairment

• Palmoplantar keratoderma, characterized by diffuse hyperkeratosis of the hands and feet [Richard et al 1998 , Heathcote et al 2000]

• Keratitis-ichthyosis-deafness (KID) syndrome, an ectodermal dysplasia characterized by vascularizing keratitis, progressive erythrokeratoderma, and profound sensorineural hearing loss as well as scarring alopecia and predisposition to squamous cell carcinoma [Richard et al 2002 , van Geel et al 2002 , van Steensel et al 2002]. KID is caused by heterozygous mutations in GJB2.

• Hystrix-like ichthyosis-deafness (HID) syndrome, an autosomal-dominant inherited keratinizing disorder characterized by sensorineural hearing loss and hyperkeratosis of the skin. Shortly after birth, erythroderma develops, with spiky and cobblestone-like hyperkeratosis of the entire skin surface appearing by one year of age. Severe palmoplantar keratoderma and scarring alopecia occur in some. HID syndrome is considered to differ from KID syndrome in: (1) the extent and time of occurrence of skin symptoms; (2) the severity of keratitis; and (3) electron microscopic features. KID syndrome and HID syndrome are caused by the same mutation in GJB2 [van Geel et al 2002].

• Vohwinkel syndrome, an autosomal dominant condition classified as a "mutilating" diffuse keratoderma because circumferential hyperkeratosis of the digits can lead to autoamputation. Mild-to-moderate sensorineural hearing loss is often associated with the disease [Maestrini et al 1999].

  Note: The M34T mutation described in a family with palmoplantar keratoderma and autosomal dominant sensorineural deafness [Kelsell et al 1997] is not a cause of dominant hearing loss [Cucci et al 2000]. This same DNA variant has been identified in normal hearing persons [Scott et al 1995 , Denoyelle et al 1998 , Kelley et al 1998], and a screen of 128 grandparents or heads of individual families not known to be related and included in CEPH (Centre d'Etude du Polymorphisme Humain) identified three individuals (2.3%) with the mutation [unpublished data].

With some mutations of GJB2, the epidermal disease and hearing loss cosegregate, while with other mutations, the severity of the disease phenotype varies, suggesting that other factors modify gene expression [Kelsell et al 2001 , Feldmann et al 2005].

GJB6

• Clouston syndrome , autosomal dominant ectodermal dysplasia, alopecia, palmoplantar hyperkeratosis [Smith et al 2002]

Clinical Description

Natural History

The four missense mutations of GJB2 (W44C, R75Q, R75W, and C202F) that cause deafness at the DFNA3 locus are associated with two different audioprofiles [Denoyelle et al 2002 , Feldmann et al 2005]. Deafness appears prelingually with the W44C, R75Q, and R75W mutations. The W44C audioprofile is characterized by a bilaterally symmetrical sensorineural loss that varies from mild to profound and affects all frequencies, while with the R75Q and R75W mutations, the hearing loss is usually greater (mean R75Q threshold 105 dbHL for both ears).

In contrast, deafness related to the C202F mutation 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 [Denoyelle et al 2002].

Tests of vestibular function and computed tomography of the temporal bones in persons segregating these mutations have been normal [Denoyelle et al 2002].

Penetrance

The pathogenicity of the R75W mutation is somewhat unclear, as it has been reported in one of 77 Egyptian controls whose hearing status was not reported [Richard et al 1998].

Nomenclature

DFNA followed by a suffix integer is used to designate loci for autosomal dominant nonsyndromic deafness. Mutations in GJB2 are associated with deafness at the DFNA3 locus.

Prevalence

The relative prevalence of DFNA3 as a cause of autosomal dominant nonsyndromic hearing loss is not known, but it is extremely rare [Van Camp et al 1997]. To date, only a few families with DFNA3 have been described [Denoyelle et al 2002].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Other causes of post-lingually acquired forms of hearing loss need to be considered (see Hereditary Hearing Loss and Deafness 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].

  Molecular genetic testing of the EYA1 gene detects mutations in approximately 40% of persons with the clinical diagnosis of BOR syndrome.

• 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 upon the presence of sensorineural hearing loss, pigmentary changes, and calculation of the W index to identify dystopia canthorum. Molecular genetic testing by sequencing of the PAX3 gene detects over 90% of deafness-causing mutations.

Management

Evaluations at Initial Diagnosis to Establish the Extent of Involvement

• A complete assessment of auditory acuity using age-appropriate tests like ABR testing, auditory steady-state response (ASSR) testing and/or pure tone audiometry

Treatment of Manifestations

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

Surveillance

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

Therapies Under Investigation

• No therapies are currently under investigation.
• In mice deafened by expression of the R75W allelic variant of GJB2, RNA interference can prevent the development of hearing loss [Maeda et al 2005].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

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 disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is extrememly small.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include assessment of auditory acuity using ABR emission testing and pure tone audiometry and medical history and physical examination to rule out other systemic findings.

Sibs of a proband

• The risk to sibs depends upon the genetic status of the proband's parents.
• If one of the proband's parents has a deafness-causing allele, 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 mutation causing DFNA3 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 mutant allele.

Other family members of a proband.  The risk to other family members depends upon the status of the proband's parents. If a parent is found to be 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 gene should be considered so that appropriate and early support and management can be provided to the child and the family. Molecular genetic testing for the mutation can only be considered if a deafness-causing mutation has been identified in an affected family member. Additional points to considerare 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 deafness 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.

Considerations in families with an apparent de novo mutation.  When neither parent of a proband with an autosomal dominant condition has the mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

DNA banking.   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 deaf individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal testing for pregnancies at 50% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The mutation in GJB2 or GJB6 causing DFNA3 in a parent must be identified before prenatal testing can be performed.

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

Requests for prenatal testing for conditions such as 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, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the deafness-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

GJB2

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

Pathologic allelic variants: The R75Q and R75W mutations are the only de novo mutations of GJB2 that have been described [Feldmann et al 2005]; both mutations are implicated in autosomal dominant nonsyndromic hearing loss and syndromic hearing loss associated with skin disorders [Janecke et al 2001 , Feldmann et al 2005]. Rouan et al (2001) hypothesize that the skin manifestations associated with these and other dominant deafness-causing GJB2 mutations reflect the trans-dominant interference of these mutations with the function of CX43 (encoded by GJA1) in areas where both CX26 and CX43 are expressed. These regions of epidermal co-expression are limited to the skin of the palms and soles thus explaining the restricted dermal phenotype. (For more information, see Genomic Databases table above.)

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 [Zhang & Nicholson 1994].

Each connexin protein contains two extracellular (E1-E2), four transmembrane (M1-M4), and three cytoplasmic domains. Each extracellular domain contains three cysteine residues joined between the E1 and E2 loops by at least one disulfide bond [Goodenough et al 1996]. 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 amphipatic and lines the putative wall of the intercellular channel [Bruzzone et al 1996], 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 composed of the same connexin, the channel is homotypic; if each connexon is formed by a different connexin, it is heterotypic. With the exception of Cx26, all connexins are phosphoproteins [Goodenough et al 1996]. Cx26 forms functional combinations with itself, Cx32, Cx46, and Cx50 [Bruzzone et al 1996].

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. Only a few GJB2 abnormal allelic variants have been tested in recombinant expression systems. The R75W mutation interfers with the CX26 gap junction activity in a Xenopus oocytes model system [Richard et al 1998].

GJB6

Normal allelic variants: 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 is 261 amino acids long.

Pathologic allelic variants: Pathologic allelic variants of GBJ6 are associated with DFNB1, DFNA3, and hidrotic ectodermal dysplasia (Clouston syndrome). The DFNB1 mutations of GJB6 are large deletions that involve most of the gene and the up-stream region [Del Castillo et al 2003 , Del Castillo et al 2005]. (For more information, see Genomic Databases table above.)

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

Abnormal gene product: Of the two deletions ( GJB6-D13S1830 and GJB6-D13S1854) truncating GJB6 that segregate in trans with GJB2 deafness-causing alleles, GJB6-D13S1830 is most frequent in Spain, France, the United Kingdom, Israel and Brazil (Portuguese origin), where it accounts for 5.9% to 8.3% of all the DFNB1 alleles. Its frequency is lower in Belgium and Australia (1.3-1.4%), and it has not been found among deaf Italian GJB2 heterozygotes. In the USA, its frequency is 1.6% to 4.0% [Del Castillo et al 2003].

GJB6-D13S1854 accounts for approximately 25% of the deaf GJB2 heterozygotes, which remained unresolved after screening for GJB6-D13S1830 in Spain, 22.2% in the United Kingdom, 6.3% in Brazil, and 1.9% in Northern Italy. This deletion has not been found in deaf GJB2 heterozygotes from France, Belgium, Israel, the Palestinian Authority, the United States, or Australia. Haplotype analysis has revealed a common founder for the mutation in Spain, Italy, and the United Kingdom [Del Castillo et al 2005].

Resources

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References

Published Statements and Policies Regarding Genetic Testing

• American College of Medical Genetics (2002) Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel (pdf).
  
  
• American College of Medical Genetics (2000) Statement on universal newborn hearing screening (pdf)

Literature Cited

• Bruzzone R, White TW, Paul DL (1996) Connections with connexins: the molecular basis of direct intercellular signaling. Eur J Biochem 238:1-27 [Medline]
  
  
• Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoort VS, Schwartz CE, Smith RJ (2004) Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat 23:582-9 [Medline]
  
  
• Cucci RA, Prasad S, Kelley PM, Green GE, Storm K, Willocx S, Cohn ES, Van Camp G, Smith RJ (2000) The M34T allele variant of connexin 26. Genet Test 4:335-44 [Medline]
  
  
• del Castillo FJ, Rodriguez-Ballesteros M, Alvarez A, Hutchin T, Leonardi E, de Oliveira CA, Azaiez H, Brownstein Z, Avenarius MR, Marlin S, Pandya A, Shahin H, Siemering KR, Weil D, Wuyts W, Aguirre LA, Martin Y, Moreno-Pelayo MA, Villamar M, Avraham KB, Dahl HH, Kanaan M, Nance WE, Petit C, Smith RJ, Van Camp G, Sartorato EL, Murgia A, Moreno F, del Castillo I (2005) A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J Med Genet 42:588-94 [Medline]
  
  
• Del Castillo I, Moreno-Pelayo MA, Del Castillo FJ, Brownstein Z, Marlin S, Adina Q, Cockburn DJ, Pandya A, Siemering KR, Chamberlin GP, Ballana E, Wuyts W, Maciel-Guerra AT, Alvarez A, Villamar M, Shohat M, Abeliovich D, Dahl HH, Estivill X, Gasparini P, Hutchin T, Nance WE, Sartorato EL, Smith RJ, Van Camp G, Avraham KB, Petit C, Moreno F (2003) Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. Am J Hum Genet 73:1452-8 [Medline]
  
  
• Denoyelle F, Lina-Granade G, Plauchu H, Bruzzone R, Chaib H, Levi-Acobas F, Weil D, Petit C (1998) Connexin 26 gene linked to a dominant deafness. Nature 393:319-20 [Medline]
  
  
• Denoyelle F, Lina-Granade G, Petit C (2002) DFNA3. Adv Otorhinolaryngol 61:47-52 [Medline]
  
  
• DeStefano AL, Cupples LA, Arnos KS, Asher JH Jr, Baldwin CT, Blanton S, Carey ML, da Silva EO, Friedman TB, Greenberg J, Lalwani AK, Milunsky A, Nance WE, Pandya A, Ramesar RS, Read AP, Tassabejhi M, Wilcox ER, Farrer LA (1998) Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations. Hum Genet 102:499-506 [Medline]
  
  
• Feldmann D, Denoyelle F, Blons H, Lyonnet S, Loundon N, Rouillon I, Hadj-Rabia S, Petit C, Couderc R, Garabedian EN, Marlin S (2005) The GJB2 mutation R75Q can cause nonsyndromic hearing loss DFNA3 or hereditary palmoplantar keratoderma with deafness. Am J Med Genet A 137:225-7 [Medline]
  
  
• Goodenough DA, Goliger JA, Paul DL (1996) Connexins, connexons, and intercellular communication. Annu Rev Biochem 65:475-502 [Medline]
  
  
• Grifa A, Wagner CA, D'Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, Rabionet R, Arbones M, Monica MD, Estivill X, Zelante L, Lang F, Gasparini P (1999) Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet 23:16-8 [Medline]
  
  
• Harris AL and Bevans CG (2001) Exploring hemichannel permeability in vitro. Methods Mol Biol 154:357-77 [Medline]
  
  
• Heathcote K, Syrris P, Carter ND, Patton MA (2000) A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350). J Med Genet 37:50-1 [Medline]
  
  
• Janecke AR, Nekahm D, Loffler J, Hirst-Stadlmann A, Muller T, Utermann G (2001) De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss. Hum Genet 108:269-70 [Medline]
  
  
• Kelley PM, Harris D, Comer B, et al (1998) Eight novel mutations of connexin 26 (GJB2) in families of non syndromic hearing loss [abstract]. Assoc Res Otolaryngol Abs 183
  
  
• Kelsell DP, Di WL, Houseman MJ (2001) Connexin mutations in skin disease and hearing loss. Am J Hum Genet 68:559-68 [Medline]
  
  
• Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM (1997) Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387:80-3 [Medline]
  
  
• Maeda Y, Fukushima K, Nishizaki K, Smith RJ (2005) In vitro and in vivo suppression of GJB2 expression by RNA interference. Hum Mol Genet 14:1641-50 [Medline]
  
  
• Maestrini E, Korge BP, Ocana-Sierra J, Calzolari E, Cambiaghi S, Scudder PM, Hovnanian A, Monaco AP, Munro CS (1999) A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families. Hum Mol Genet 8:1237-43 [Medline]
  
  
• Morle L, Bozon M, Alloisio N, Latour P, Vandenberghe A, Plauchu H, Collet L, Edery P, Godet J, Lina-Granade G (2000) A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss. J Med Genet 37:368-70 [Medline]
  
  
• Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynanen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, Russell L (2002) Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet 70:1341-8 [Medline]
  
  
• Richard G, White TW, Smith LE, Bailey RA, Compton JG, Paul DL, Bale SJ (1998) Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma. Hum Genet 103:393-9 [Medline]
  
  
• Rouan F, White TW, Brown N, Taylor AM, Lucke TW, Paul DL, Munro CS, Uitto J, Hodgins MB, Richard G (2001) trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. J Cell Sci 114:2105-13 [Medline]
  
  
• Scott DA, Carmi R, Elbedour K, Duyk GM, Stone EM, Sheffield VC (1995) Nonsyndromic autosomal recessive deafness is linked to the DFNB1 locus in a large inbred Bedouin family from Israel. Am J Hum Genet 57:965-8 [Medline]
  
  
• Smith FJ, Morley SM, McLean WH (2002) A novel connexin 30 mutation in Clouston syndrome. J Invest Dermatol 118:530-2 [Medline]
  
  
• Smith RJ, Bale JF Jr, White KR (2005) Sensorineural hearing loss in children. Lancet 365:879-90 [Medline]
  
  
• Van Camp G, Willems PJ, Smith RJ (1997) Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet 60:758-64 [Medline]
  
  
• van Geel M, van Steensel MA, Kuster W, Hennies HC, Happle R, Steijlen PM, Konig A (2002) HID and KID syndromes are associated with the same connexin 26 mutation. Br J Dermatol 146:938-42 [Medline]
  
  
• van Steensel MA, van Geel M, Nahuys M, Smitt JH, Steijlen PM (2002) A novel connexin 26 mutation in a patient diagnosed with keratitis- ichthyosis-deafness syndrome. J Invest Dermatol 118:724-7 [Medline]
  
  
• Zhang JT and Nicholson BJ (1994) The topological structure of connexin 26 and its distribution compared to connexin 32 in hepatic gap junctions. J Membr Biol 139:15-29 [Medline]
  
  

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