Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans
Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans
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DOI：
10.1093/hmg/6.9.1605
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发表时间：
1997-09-01
影响因子：
3.5
通讯作者：
Fortina, P
中科院分区：
文献类型：
--
作者：
Zelante, L;Gasparini, P;Fortina, P
非综合征型感觉神经性常染色体隐性遗传性耳聋（NSRD）是遗传性听力损失的最常见形式。既往研究定义：至少15个人类NSRD基因座。最近，我们证明了位于13号染色体长臂上的Khat DFNB 1与地中海地区80%的病例相似，现在用额外的标记进行进一步分析鉴定了几个重组体，这些重组体将候选区域缩小到类似于5cM，由标记D13S141和D13S232包围，并包括几个EST和候选基因，包括连接蛋白26（GJB 2）基因，对患者DNA的PCR产物分析显示，连接蛋白26基因存在两个移码突变，GJB2 cDNA第35位6个G内的一个G缺失（突变35delG）导致过早的链终止，并且存在于63%的NSRD染色体中，证明与13号染色体连锁，GJB 2的167位处的T缺失在另一名患者中检测到了也导致过早链终止的突变（167delT）。还鉴定了4个中性序列多态性。这些发现与最近的一项研究一致，该研究表明连接蛋白26基因的突变与三个巴基斯坦家庭的遗传性耳聋相关，并且GJB 2是DFNB 1。连接蛋白26是参与缝隙连接形成的蛋白质大家族的成员，缝隙连接参与电突触和相邻细胞之间小分子和离子电流的直接转移。GJB2作为DFNB 1基因的鉴定应该提供对正常和异常听力的生物学的更好理解，有助于形成诊断的基础，并可能有助于制定治疗这种常见遗传疾病的策略。
Non-syndromic neurosensory autosomal recessive deafness (NSRD) is the most common form of genetic hearing loss. Previous studies defined at: least 15 human NSRD loci. Recently we demonstrated Khat DFNB1, located on the long arm of chromosome 13, accounts for similar to 80% of cases in the Mediterranean area, Further analysis with additional markers now identifies several recombinants which narrow the candidate region to similar to 5 cM, encompassed by markers D13S141 and D13S232 and including several ESTs and candidate genes, including the connexin26 (GJB2) gene, Analysis of PCR products from our affected patients' DNA shows two frameshift mutations in the connexin26 gene, Deletion of a G within a stretch of six Gs at position 35 of the GJB2 cDNA (mutation 35delG) leads to premature chain termination and is present in 63% of NSRD chromosomes, demonstrating linkage to chromosome 13, Deletion of a T at position 167 of GJB2 (mutation 167delT), also resulting in premature chain termination, was detected in another patient, Four neutral sequence polymorphisms were also identified, These findings are in agreement with a recent study showing that mutations in the connexin26 gene are associated with genetic forms of deafness in three Pakistani families and that GJB2 is DFNB1. Connexin26 is a member of a large family of proteins involved in formation of gap junctions, which are involved in electrical synapses and the direct transfer of small molecules and ionic currents between neighboring cells, The identification of GJB2 as the DFNB1 gene should provide a better understanding of the biology of normal and abnormal hearing, help form the basis for diagnosis and may facilitate development of strategies for treatment of this common genetic disorder.