Correspondence

Molecular Mechanism of a Frequent Genetic Form of Deafness

N Engl J Med 2003; 349:716-717August 14, 2003

Article

To the Editor:

The genes encoding the two major connexins of the cochlea are contiguous on human chromosome 13 (GJB2 and GJB6) and on mouse chromosome 14 (Cx26 and Cx30, respectively). Biallelic GJB2 mutations account for a large proportion of cases of recessive deafness in many European countries,1 whereas biallelic mutations of GJB6 appear to be involved only rarely. However, del Castillo et al.2 have shown that a significant proportion of people who have severe or profound prelingual deafness carry both a deleterious point mutation in GJB2 on one chromosome and a large deletion (approximately 340 kb) in GJB6, but not GJB2, on the other chromosome. An unsolved question is whether their hearing impairment is due to the GJB2/GJB6 double heterozygous state or to the concomitant loss of another element (either a gene or a GJB2 regulatory element) located in the deletion interval.2 Mice with spontaneous or engineered mutations causing deafness have proved to be valuable models for the study of several genetic forms of hearing loss in humans.3

We addressed the above issue by studying Cx26 ^+/–/Cx30 ^+/–, double heterozygous mice that were obtained by mating Cx26 ^+/–and either Cx30 ^+/– or Cx30 ^–/–knockout mice.4,5 We have previously reported that Cx30 ^–/– mice have severe hearing impairment and complete loss of the endocochlear potential (i.e., the transepithelial difference in electric potential between the endolymphatic and perilymphatic compartments).5 We found that one-month-old double heterozygous mice, which carry single functional Cx26 and Cx30 alleles, have a moderate hearing impairment (auditory brain-stem–response threshold for a click stimulus, 53±11 dB sound-pressure level [in eight ears], vs. 30±0 dB sound-pressure level in Cx26 ^+/–/Cx30 ^+/+ littermates [in eight ears] and Cx26 ^+/+/Cx30 ^+/– littermates [in eight ears]; P<0.001 for both comparisons). In addition, their endocochlear potential (44±10 mV [in 10 ears]) was approximately half that measured in Cx26 ^+/– single heterozygotes (82±8 mV [in 10 ears]) and Cx30 ^+/– single heterozygotes (78±3 mV [in 8 ears]) (P<0.001). No structural anomaly of the cochlear tissues was detected by histologic analysis, and the endolymphatic potassium concentration (148±3 mmol per liter [in 10 ears]) was normal.

We conclude that the functional loss of one GJB2 allele and one GJB6 allele probably contributes to the aforementioned hearing impairment in humans but is not sufficient to account for severe hearing loss. Moreover, because double heterozygous mice have a lower endocochlear potential than Cx30 ^+/– heterozygotes, our results indicate that not only Cx30 (GJB6) 5 but also Cx26 (GJB2) is involved in the production of the endocochlear potential.

Vincent Michel, Ph.D.
Jean-Pierre Hardelin, M.D., Ph.D.
Christine Petit, M.D., Ph.D.
Institut Pasteur, 75724 Paris CEDEX 15, France

5 References

1. 1

   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 counseling. Lancet 1999;353:1298-1303
   CrossRef | Web of Science | Medline

2. 2

   del Castillo I, Villamar M, Moreno-Pelayo MA, et al. A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med 2002;346:243-249
   Full Text | Web of Science | Medline

3. 3

   Petit C, Levilliers J, Hardelin J-P. Molecular genetics of hearing loss. Annu Rev Genet 2001;35:589-646
   CrossRef | Web of Science | Medline

4. 4

   Gabriel HD, Jung D, Butzler C, et al. Transplacental uptake of glucose is decreased in embryonic lethal connexin26-deficient mice. J Cell Biol 1998;140:1453-1461
   CrossRef | Web of Science | Medline

5. 5

   Teubner B, Michel V, Pesch J, et al. Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential. Hum Mol Genet 2003;12:13-21
   CrossRef | Web of Science | Medline

Citing Articles (5)

Citing Articles

1. 1

   Mohsen Esmaeili, Mortaza Bonyadi, Mohammad Nejadkazem. (2007) Common mutation analysis of GJB2 and GJB6 genes in affected families with autosomal recessive non-syndromic hearing loss from Iran: Simultaneous detection of two common mutations (35delG/del(GJB6-D13S1830)) in the DFNB1-related deafness. International Journal of Pediatric Otorhinolaryngology 71:6, 869-873
   CrossRef

2. 2

   Kenneth R. Johnson, Qing Yin Zheng, Konrad Noben-Trauth. (2006) Strain background effects and genetic modifiers of hearing in mice. Brain Research 1091:1, 79-88
   CrossRef

3. 3

   Christine Petit. (2006) From deafness genes to hearing mechanisms: harmony and counterpoint. Trends in Molecular Medicine 12:2, 57-64
   CrossRef

4. 4

   J. E. A. Common, M. Bitner-Glindzicz, E. A. O'Toole, M. R. Barnes, L. Jenkins, A. Forge, D. P. Kelsell. (2005) Specific loss of connexin 26 expression in ductal sweat gland epithelium associated with the deletion mutation del(GJB6-D13S1830). Clinical and Experimental Dermatology 30:6, 688-693
   CrossRef

5. 5

   P. Seeman, O. Bendova, D. Raskova, M. Malikova, D. Groh, Z. Kabelka. (2005) Double Heterozygosity with Mutations Involving both the GJB2 and GJB6 Genes is a Possible, but very Rare, Cause of Congenital Deafness in the Czech Population. Annals of Human Genetics 69:1, 9-14
   CrossRef