Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss
Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss
复制标题
DOI：
10.1086/301807
复制
发表时间：
1998-04-01
影响因子：
9.8
通讯作者：
Kimberling, WJ
中科院分区：
文献类型：
--
作者：
Kelley, PM;Harris, DJ;Kimberling, WJ
连接蛋白26（Cx26）基因（GJB2）突变与常染色体隐性遗传非综合征性感觉神经性耳聋（称为"DFNB 1"）有关。“研究表明，DFNB 1（13q11 - 12）导致20%的儿童耳聋，携带率可能高达2.8%。本研究分析了58个多重家庭，每个家庭至少有两个受影响的儿童被诊断为常染色体隐性遗传性非综合征性耳聋。在58个家系中，有20个家系在Cx26的两个等位基因中都有突变。116条染色体中有33条含有30delG等位基因，频率为0.284。在192条对照染色体中的2条中观察到这种突变，估计基因频率为.01 +/-.007。然后估计30delG等位基因的纯合频率为0.0001或1/10，000。鉴于所有儿童听力障碍的频率为1/1，000，其中一半是遗传性的，特定突变30delG负责所有儿童听力损失的10%和所有儿童遗传性听力损失的20%。在受影响的人群中还观察到六种新的突变。检测到的缺失会导致严重破坏蛋白质结构的移码。观察到三个新的错义突变，Val84Met，Val95Met和Ser113Pro。错义突变101 T--> C已被报道为DFNA 3的显性等位基因，DFNA 3是一种显性非综合征性听力损失。数据进一步支持这一发现，这种突变不会导致显性听力损失。这个等位基因被发现在一个隐性的家庭分离独立的听力损失表型和192个控制染色体中的3个。这些结果表明，101T--> C不足以导致听力损失。
Mutations in the connexin 26 (Cx26) gene (GJB2) are associated with the type of autosomal recessive nonsyndromic neurosensory deafness known as "DFNB1." Studies indicate that DFNB1 (13q11-12) causes 20% of all childhood deafness and may have a carrier rate as high as 2.8%. This study describes the analysis of 58 multiplex families each having at least two affected children diagnosed with autosomal recessive nonsyndromic deafness. Twenty of the 58 families were observed to have mutations in both alleles of Cx26. Thirty-three of 116 chromosomes contained a 30delG allele, for a frequency of .284. This mutation was observed in 2 of 192 control chromosomes, for an estimated gene frequency of .01 +/- .007. The homozygous frequency of the 30delG allele is then estimated at .0001, or 1/10,000. Given that the frequency of all childhood hearing impairment is 1/1,000 and that half of that is genetic, the specific mutation 30delG is responsible for 10% of all childhood hearing loss and for 20% of all childhood hereditary hearing loss. Six novel mutations were also observed in the affected population. The deletions detected cause frameshifts that would severely disrupt the protein structure. Three novel missense mutations, Val84Met, Val95Met, and Ser113Pro, were observed. The missense mutation 101T-->C has been reported to be a dominant allele of DFNA3, a dominant nonsyndromic hearing loss. Data further supporting the finding that this mutation does not cause dominant hearing loss are presented. This allele was found in a recessive family segregating independently from the hearing-loss phenotype and in 3 of 192 control chromosomes. These results indicate that 101T-->C is not sufficient to cause hearing loss.