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Different functional consequences of two missense mutations in the GJB2 gene associated with non-syndromic hearing loss.

 Soo-Young Choi  ;  Hong-Joon Park  ;  Kyu Yup Lee  ;  Emilie Hoang Dinh  ;  Qing Chang  ;  Shoab Ahmad  ;  Sang Heun Lee  ;  Jinwoong Bok  ;  Xi Lin  ;  Un-Kyung Kim 
 HUMAN MUTATION, Vol.30(7) : 716-727, 2009 
Journal Title
Issue Date
Cell Line ; Connexin 26 ; Connexins/genetics* ; Family Health ; Gap Junctions/genetics ; Genes, Dominant ; Genes, Recessive ; Hearing Loss/genetics* ; Humans ; Korea ; Mutation, Missense* ; Protein Transport ; Transfection
hearing loss ; connexin26 ; GJB2 ; gap junction ; mutation ; hemichannel
Mutations in the GJB2 gene, which encodes the gap junction (GJ) protein connexin26 (Cx26), are the most common cause of inherited non-syndromic hearing loss (NSHL). We identified two missense mutations, p.D46E (c.138T>G) and p.T86R (c.257C>G), of GJB2 in Korean HL families. The novel p.D46E mutation exhibited autosomal dominant inheritance, while the p.T86R mutation, which is exclusively found in Asians, segregated with an autosomal recessive pattern. Thus, we sought to elucidate the pathogenic nature of such different inherited patterns of HL. We studied protein localization and gap junction functions in cells transfected with wild-type or mutant Cx26 tagged with fluorescent proteins, which allowed visual confirmation of homozygous or heterozygous mutant GJs. The Cx26-D46E mutant was targeted to the plasma membrane, but this mutant protein failed to transfer Ca(2+) or propidium iodide intercellularly, suggesting disruption of both ionic and biochemical coupling. Heterozygous GJs also showed dysfunctional intercellular couplings and hemichannel opening, confirming the dominant-negative nature of the p.D46E mutation. The Cx26-T86R mutant protein did not form GJs, since the mutated protein was confined in the cytoplasm and not transported to the cell membrane. When Cx26-T86R was co-expressed with Cx26-WT, ionic and biochemical coupling was normal, consistent with the recessive nature of the mutation. These studies revealed distinct pathogenic mechanisms of two GJB2 mutations identified in Korean families.
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1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
Bok, Jin Woong(복진웅) ORCID logo https://orcid.org/0000-0003-1958-1872
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