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Hearing loss and connexin 26

Martijn H Kemperman MD   Lies H Hoefsloot PhD  ¹   Cor W R J Cremers MD PhD  

Department of Otorhinolaryngology, University Medical Centre St Radboud, Nijmegen, The Netherlands
¹ Department of Medical Genetics, University Medical Centre St Radboud, Nijmegen, The Netherlands

Correspondence to: Dr CWRJ Cremers, Department of Otorhinolaryngology, University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, The NetherlandsE-mail: D.Helsper{at}kno.azn.nl

	INTRODUCTION

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 
Hearing impairment is a sensory disability that affects millions of people all over the world. Though not life-threatening, it can become a major burden in social and professional life. In the industrialized world, deafness of infective and/or environmental origin has become less frequent, with a consequent rise in the proportion of hereditary hearing impairment. Deafness occurs in 1:1000 neonates¹ and the cause is hereditary in about half. This type of hearing impairment is sometimes referred to as prelingual, as it affects the child before the age of speech development. A distinction can be made between syndromic deafness, in which the deafness is accompanied by other specific abnormalities, and non-syndromic deafness (about 75%), in which there are no additional abnormalities. Approximately three-quarters of the non-syndromic forms are caused by a recessive disorder^{1,2,3,4. Table 1} gives an overview of some epidemiological features.

View this table: [in this window] [in a new window]   Table 1. Epidemiological features of prelingual hearing loss

 

Between 1997 and today, many non-syndromic hereditary forms of deafness have been localized on the human genome by genetic linkage techniques. Depending on the pattern of inheritance of the deafness, these loci are designated DFNA (autosomal dominant), DFNB (autosomal recessive) or DFN (X-linked). They are numbered in chronological order of discovery. For the majority of these loci the underlying disease-causing genes have not been identified so far. On the Hereditary Hearing Loss Homepage⁵ all these currently known forms of hereditary deafness are summarized. Tables 2,3,4,5, derived from this homepage, illustrate the achievements in this field of research. Certain research groups, having found preliminary evidence of a new locus, have claimed (‘reserved’) loci in advance. ‘Withdrawn’ indicates those which turned out not to be correct. Most of these genetic types of hearing impairment are quite rare, with the exception of DFNB1. This paper addresses DFNB1, which is caused by mutations in the connexin 26 gene.

View this table: [in this window] [in a new window]   Table 2. Loci and genes associated with autosomal dominant non-syndromic hearing impairment, with the year of publication

 

View this table: [in this window] [in a new window]   Table 3. Loci and genes associated with autosomal recessive non-syndromic hearing impairment, with the year of publication

 

View this table: [in this window] [in a new window]   Table 4. Loci and genes associated with X-linked non-syndromic hearing impairment, with the year of publication

 

View this table: [in this window] [in a new window]   Table 5. Mitochondrial mutations associated with non-syndromic hearing impairment, with the year of publication

 

	HEARING IMPAIRMENT

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 
Although the connexin 26 gene GJB2 is also involved in an autosomal dominant form of deafness (DFNA3), most mutations in this gene cause recessive hereditary bilateral deafness/hearing impairment, so-called DFNB1. This form of sensorineural non-syndromic hearing loss is prelingual and its severity varies from mild to profound, depending to some extent on the type of mutation^6,7. Hearing loss in the high-tone range has recently been described as a characteristic feature, but all frequencies are affected⁸. In two-thirds of cases, the hearing loss is non-progressive and there are usually no vestibular and/or labyrinthine abnormalities.

	GENETICS

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 
DFNB1 was the first locus incriminated in autosomal recessive deafness; in 1997 GJB2 was found to be responsible⁹. GJB2 is a small gene situated on chromosome 13q11; it has a length of about 5.5 kilobases. There are two exons, of which only one contains the coding sequence. The mRNA is 2.4 kilobases long and translates into a protein with 226 aminoacids. This protein belongs to the connexin family, which currently has more than a dozen members¹⁰.

	THE PROTEIN (FIGURE 1)

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 
Connexins are membrane proteins with four transmembrane domains. Six chains of these proteins form a complex (a hexamer), called connexon. Two hexamers in the membranes of adjacent cells form a cell-to-cell channel, a so-called gap junction, which allows the transport of small molecules and ions between cells. A hexamer can contain various types of connexin, and various types of hexamer can form cell-to-cell channels. The channel constituents determine which molecules or ions can pass through¹¹.

View larger version (123K): [in this window] [in a new window]   Figure 1. Schematic representation of a gap junction. Six connexins form a connexon. Two connexons of neighbouring cells form pores, which allow intercellular transport of small molecules (Adapted from Ref. 22)

 

	THE CELL (FIGURE 2)

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 
Recently, the hypothesis was put forward that CX26 protein is essential for maintaining the high K⁺ concentration in the endolymph of the inner ear. Sound stimulation of the ossicular chain causes vibrations in the endolymph. K⁺ ions enter the hair cells under the influence of these vibrations and the vibration signal is ultimately converted into a neural signal. The system is regenerated by the release of K⁺ from the hair cells into the supporting cells. The K⁺ ions are then passed from cell to cell via gap junctions and are eventually released into the endolymph. Except for sensorineural cells, the CX26 protein is present in gap junctions connecting all cell types in the cochlea, including the spiral limbus, the supporting cells, the spiral ligament and the basal and intermediate cells of the stria vascularis. It is therefore very likely that connexin 26 is involved in K⁺-recycling in the cochlea¹¹.

View larger version (66K): [in this window] [in a new window]   Figure 2. Schematic section through the human cochlea showing K+ recycling pathway and the expression of connexin 26 (GJB2). (Adapted from Ref. 23)

 

	EPIDEMIOLOGY

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 
Mutations in CX26 are the most common cause of autosomal recessive deafness throughout the world. This gene is believed relevant to half of all cases of hereditary deafness. CX26 shows diverse mutations, but one mutation occurs very frequently in Europe—the 35delG mutation. Average carrier frequency in Europe is 1:51 (north/middle Europe 1:79, south Europe 1:35)^{12 (Table 6}). In the Mediterranean countries the carrier frequency exceeds even that of the F508 mutation in the CFTR gene which causes cystic fibrosis. Carrier frequencies in North America and Australia are comparable to those in north/middle Europe. In oriental populations and Ashkenazi Jews, other mutations in the same gene play a more important role (234delC¹³ and 176delT¹⁴, respectively). The high frequency of connexin-26-related hearing impairment in certain populations may be the result of the tradition of marriages between hearing-impaired persons¹⁵. The 35delG mutation gives rise to a severely shortened, non-functional protein¹⁶. More than sixty other, far less frequent, mutations have been described in CX26¹⁷. Uncertainty about the pathogenicity of some of the mutations complicates interpretation of mutation analysis¹⁸.

View this table: [in this window] [in a new window]   Table 6. Carrier frequency of mutation 35delG in the GJB2 gene in 17 European countries (adapted from Ref. 12)

 

Denoyelle et al.⁷ found mutations in the CX26 gene in 49% of the families from France, Great Britain and New Zealand who had severe to profound prelingual hearing loss. CX26 mutations were present in 51% of the group with, versus 31% in the group without, a clear familial history of hearing impairment; 86% of the CX26 mutations were 35delG mutations. Mueller et al.¹⁹ studied a group of 284 English patients with early childhood hearing impairment or deafness, with and without hereditary causes. They found CX26 mutations in 27.8% of the familial cases and in 7.9% of the sporadic cases; 70% of the CX26 mutations were 35delG mutations. This difference can be explained by the fact that families with different ethnic backgrounds were included in the study. The prevalence of non-familial, sporadic hearing impairment based on CX26 mutations in an English—Belgian population of 68 children was 10%²⁰.

	DIAGNOSIS

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 
An increasing number of medical centres can perform mutation analysis to determine involvement of the CX26 gene in congenital hearing impairment. This method has been available for several years at the department of medical genetics in Nijmegen. We retrospectively analysed the outcome of ninety-one CX26 mutation analysis requests covering a fixed period of time. Nineteen unrelated cases were shown to have two mutations in the gene. Twelve of them turned out to be homozygous, whereas four others were heterozygous for the 35delG mutation. Overall, the 35delG mutation was involved in 84% of the cases; thirteen cases originated from multiaffected families, whereas three others were sporadic cases. Information on the remaining three families could not be retrieved. Table 7 gives an overview of the CX26 mutations found in Nijmegen.

View this table: [in this window] [in a new window]   Table 7. Overview of CX26 mutations found in Nijmegen

 

Mutation analysis applies not only to children with a clear family history, but also to children whose parents have normal hearing (sporadic cases). Moreover, if a mutation in CX26 is present, genetic counselling can be offered to provide information on the aetiology answers and on the likelihood of recurrence in future offspring. When a mutation analysis is positive there will usually be no need for further investigations such as imaging and ophthalmological tests, because other causes of congenital deafness no longer have to be excluded. In these cases, attention can immediately be focused on optimizing the child's hearing. Histopathological examination of the cochlea in a patient with confirmed CX26 mutation has revealed an intact acoustic nerve²¹. This means that these patients are suitable candidates for cochlear implantation, provided that their hearing loss is sufficiently profound. Early diagnosis leads to early treatment, which gives the best results with cochlear implantation.

	CONCLUSION

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 
Unlike many other genes CX26 is small, so that screening for mutations is fast and relatively simple. Besides, the overall high involvement of CX26 mutations in autosomal recessive non-syndromic forms of deafness, and even in sporadic cases, makes mutation analysis distinctly worth-while. CX26 mutation analysis has therefore secured a place as a useful tool in clinical practice. So far, many different mutations in the CX26 gene causing DFNB1 have been identified¹⁷. The uncertainty about the pathogenicity of the mutation demands close collaboration with geneticists who are familiar with deafness¹⁸. Nevertheless, CX26 mutation analysis provides a good starting-point in the molecular diagnosis of patients with non-syndromic congenital deafness.

	Acknowledgments

 
This work was supported by the Dutch Organisation for Scientific Research, council for medical and health research (project No. 920-03-100) and the ENT-Research Foundation Nijmegen, The Netherlands. The text is based on an article published in Nederlands Tijdschrift Voor Geneeskunde.

	REFERENCES

TOP INTRODUCTION HEARING IMPAIRMENT GENETICS THE PROTEIN (FIGURE 1) THE CELL (FIGURE 2) EPIDEMIOLOGY DIAGNOSIS CONCLUSION REFERENCES

 

1. Morton NE. Genetic epidemiology of hearing impairment. Ann N Y Acad Sci1991; 630:16 -31[Medline]

2. Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss and its Syndromes. Oxford Monographs on Medical Genetics no. 28. Oxford: Oxford University Press, 1995

3. Reardon W. Genetic deafness. J Med Genet1992; 29:521 -6[Free Full Text]

4. Parving A. Hearing disorders in childhood, some procedures for detection, identification and diagnostic evaluation. Int J Pediatr Otorhino- laryngol1985; 9:31 -57

5. Van Camp G, Smith RJH. Hereditary Hearing Loss Homepage. [http://dnalab-www.uia.ac.be/dnalab/hhh ] (accessed 22 January 2002)

6. Cohn ES, Kelley PM. Clinical phenotype and mutations in connexin 26 (DFNB1/GJB2), the most common cause of childhood hearing loss. Am J Med Genet1999; 89:130 -6[Medline]

7. Denoyelle F, Marlin S, Weil D, et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet1999; 353:1298 -303[Medline]

8. Wilcox SA, Saunders K, Osborn AH, et al. High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet2000; 106:399 -405[Medline]

9. Kelsell DP, Dunlop J, Stevens HP, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature1997; 387:80 -3[Medline]

10. Kelley PM, Cohn E, Kimberling WJ. Connexin 26: required for normal auditory function. Brain Res Brain Res Rev2000; 32:184 -88[Medline]

11. Kikuchi T, Kimura RS, Paul DL, Takasaka T, Adams JC. Gap junction systems in the mammalian cochlea. Brain Res Brain Res Rev 2000;32:163 -6[Medline]

12. Gasparini P, Rabionet R, Barbujani G, et al. High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG. Eur J Hum Genet 2000;8:19 -23[Medline]

13. Abe S, Usami S, Shinkawa H, Kelley PM, Kimberling WJ. Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet 2000;37:41 -3[Abstract/Free Full Text]

14. Morell RJ, Kim HJ, Hood LJ, et al. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness [see comments]. N Engl J Med1998; 339:1500 -5[Abstract/Free Full Text]

15. Nance WE, Liu XZ, Pandya A. Relation between choice of partner and high frequency of connexin-26 deafness. Lancet2000; 356:500 -1[Medline]

16. Zelante L, Gasparini P, Estivill X, et al. Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet 1997;6:1605 -9[Abstract/Free Full Text]

17. Estivill X, Rabionet R. The Connexin-deafness homepage World Wide Web URL: [http://www.iro.es/deafness ] (accessed November 2001)

18. Marlin S, Garabedian EN, Roger G, et al. Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counselling. Arch Otolaryngol Head Neck Surg2001; 127:927 -33

19. Mueller RF, Nehammer A, Middleton A, et al. Congenital non-syndromal sensorineural hearing impairment due to connexin 26 gene mutations—molecular and audiological findings. Int J Pediatr Otorhinolaryngol1999; 50:3 -13[Medline]

20. Lench N, Houseman M, Newton V, Van Camp G, Mueller R. Connexin-26 mutations in sporadic non-syndromal sensorineural deafness. Lancet1998; 351:415[Medline]

21. Jun AI, McGuirt WT, Hinojosa R, Green GE, Fischel-Ghodsian N, Smith RJ. Temporal bone histopathology in connexin 26-related hearing loss. Laryngoscope2000; 110:269 -75[Medline]

22. Furshpan EJ, Pooter DD. Transmission at the giant motor synapses of the crayfish. J Physiol2001; 145:289 -325

23. Steel KP, Bussoli TJ. Deafness genes: expressions of surprise. Trends Genet1999; 15:207 -11[Medline]

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