Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31

Xue Z Liu, Yongyi Yuan, Denise Yan, Emilie Hong Ding, Xiao Mei Ouyang, Yu Fei, Wenxue Tang, Huijun Yuan, Qing Chang, Li Lin Du, Xin Zhang, Guojian Wang, Shoeb Ahmad, Dong Yang Kang, Xi Lin, Pu Dai

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Abstract

Mutations in the genes coding for connexin 26 (Cx26) and connexin 31 (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/ A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric Cx26/Cx31 connexons. Furthermore, by cotransfection of mCherry-tagged Cx26 and GFP-tagged Cx31 in human embryonic kidney (HEK)-293 cells, we demonstrated that the two connexins were able to co-assemble in vitro in the same junction plaque. Together, our data indicate that a genetic interaction between these two connexin genes can lead to hearing loss.

Original languageEnglish
Pages (from-to)53-62
Number of pages10
JournalHuman Genetics
Volume125
Issue number1
DOIs
StatePublished - Jan 1 2009

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Connexins
Deafness
Mutation
Cochlea
Hearing Loss
Genes
Heterozygote
Connexin 26
human GJB3 protein
Exons
Membrane Proteins
Alleles
Kidney
DNA

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31. / Liu, Xue Z; Yuan, Yongyi; Yan, Denise; Ding, Emilie Hong; Ouyang, Xiao Mei; Fei, Yu; Tang, Wenxue; Yuan, Huijun; Chang, Qing; Du, Li Lin; Zhang, Xin; Wang, Guojian; Ahmad, Shoeb; Kang, Dong Yang; Lin, Xi; Dai, Pu.

In: Human Genetics, Vol. 125, No. 1, 01.01.2009, p. 53-62.

Research output: Contribution to journalArticle

Liu, XZ, Yuan, Y, Yan, D, Ding, EH, Ouyang, XM, Fei, Y, Tang, W, Yuan, H, Chang, Q, Du, LL, Zhang, X, Wang, G, Ahmad, S, Kang, DY, Lin, X & Dai, P 2009, 'Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31', Human Genetics, vol. 125, no. 1, pp. 53-62. https://doi.org/10.1007/s00439-008-0602-9
Liu, Xue Z ; Yuan, Yongyi ; Yan, Denise ; Ding, Emilie Hong ; Ouyang, Xiao Mei ; Fei, Yu ; Tang, Wenxue ; Yuan, Huijun ; Chang, Qing ; Du, Li Lin ; Zhang, Xin ; Wang, Guojian ; Ahmad, Shoeb ; Kang, Dong Yang ; Lin, Xi ; Dai, Pu. / Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31. In: Human Genetics. 2009 ; Vol. 125, No. 1. pp. 53-62.
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AU - Ouyang, Xiao Mei

AU - Fei, Yu

AU - Tang, Wenxue

AU - Yuan, Huijun

AU - Chang, Qing

AU - Du, Li Lin

AU - Zhang, Xin

AU - Wang, Guojian

AU - Ahmad, Shoeb

AU - Kang, Dong Yang

AU - Lin, Xi

AU - Dai, Pu

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