Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31.
Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31.
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由间隙连接蛋白 Cx26 和 Cx31 突变引起的非综合征性耳聋的双基因遗传。
DOI：
10.1007/s00439-008-0602-9
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发表时间：
2009-02
期刊：
影响因子：
5.3
通讯作者：
Dai P
中科院分区：
文献类型：
--
作者：
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
编码连接蛋白26（Cx 26）和连接蛋白31（Cx 31）的基因突变会导致非综合征性耳聋。在这里，我们提供的证据表明，在这两个连接蛋白基因的突变可以相互作用，导致听力损失的双基因杂合子在人类。我们对108例GJB 2杂合子中国患者进行了GJB 3突变的测序。我们排除了GJB 2外显子1突变和GJB 6缺失是中国杂合子先证者第二个突变等位基因的可能性。在3个无关家系（235 delC/N166 S、235 delC/A194 T和299 delAT/A194 T）中发现了与GJB 2的235 delC和299 delAT复合杂合的两种不同的GJB 3突变（N166 S和A194 T）。在200名无关的中国对照者的DNA中未检测到Cx 31的这两种突变。Cx 26与Cx 31的直接物理相互作用得到了数据的支持，这些数据表明Cx 26和Cx 31在耳蜗中具有重叠的表达模式。此外，通过小鼠耳蜗膜蛋白的免疫共沉淀，我们确定了异聚体Cx 26/Cx 31连接子的存在。此外，通过将mCherry标记的Cx 26和GFP标记的Cx 31共转染人胚肾（HEK）-293细胞，我们证明了这两种连接蛋白能够在体外共同组装在相同的连接斑块中。总之，我们的数据表明，这两个连接蛋白基因之间的遗传相互作用可能导致听力损失。
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 108GJB2heterozygous Chinese patients for mutations inGJB3by sequencing. We have excluded the possibility that mutations in exon 1 ofGJB2and the deletion ofGJB6are the second mutant allele in these Chinese heterozygous probands. Two differentGJB3mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT ofGJB2were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations inCx31was 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.
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DOI：
10.1083/jcb.129.3.805
发表时间：
1995-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Elfgang C;Eckert R;Lichtenberg-Fraté H;Butterweck A;Traub O;Klein RA;Hülser DF;Willecke K
通讯作者：
Willecke K
影响因子：
4
作者：
del Castillo, FJ;Rodríguez-Ballesteros, M;del Castillo, I
通讯作者：
del Castillo, I
影响因子：
3.9
作者：
Hamelmann, C;Amedofu, G K;Horstmann, R D
通讯作者：
Horstmann, R D
影响因子：
3.5
作者：
Liu, XZ;Xia, XJ;Nance, WE
通讯作者：
Nance, WE
影响因子：
8.8
作者：
Dai, Pu;Yu, Fei;Wong, Lee-Jun
通讯作者：
Wong, Lee-Jun