Mohseni Marzieh, Honarpour Asal, Mozafari Reza, Davarnia Behzad, Najmabadi Hossein, Kahrizi Kimia
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences (USWR), Tehran, Iran.
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences (USWR), Tehran, Iran.
Int J Pediatr Otorhinolaryngol. 2014 Nov;78(11):1828-32. doi: 10.1016/j.ijporl.2014.08.035. Epub 2014 Sep 1.
Mutations in the SLC26A4 gene cause both Pendred syndrome and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB4 locus. The SLC26A4 mutations vary among different communities. Previous studies have shown that mutations in the SLC26A4 gene are responsible for the more common syndromic hereditary hearing loss in Iran. This study assesses the possibility of a founder mutation for Pendred syndrome in northwest Iran.
In this study, we performed comprehensive clinical and genetic evaluations in two unrelated families from northwest Iran with nine members affected by hearing loss (HL). After testing short tandem repeat (STR) markers to confirm linkage to the SLC26A4 locus, we screened the SLC26A4 gene by Sanger sequencing of all 21 exons, exon-intron boundaries and the promoter region for any causative mutation. We identified the same causative mutation in these two families as we had detected earlier in two other Azeri families from northwest Iran. To investigate the possibility of a founder effect in these four families, we conducted haplotype analysis, and 14 single nucleotide polymorphisms (SNPs) throughout the SLC26A4 gene were genotyped.
Patients in the two families showed the phenotype of Pendred syndrome. A known frameshift mutation (c.965insA, p.N322Fs7X) in exon 8 was identified in the two families, which was the same mutation that we detected previously in two other Azeri families. The results of haplotype analysis showed that all 15 patients from four families shared the founder mutation. Common haplotypes were not observed in noncarrier members.
Based on the results of our two studies, the c.965insA mutation has only been described in Iranian families from northwest Iran, so there is evidence for a founder mutation originating in this part of Iran.
SLC26A4基因突变可导致 Pendred 综合征以及位于 DFNB4 位点的常染色体隐性非综合征性听力损失（ARNSHL）。SLC26A4基因突变在不同群体中存在差异。既往研究表明，SLC26A4基因突变是伊朗较为常见的综合征性遗传性听力损失的病因。本研究评估伊朗西北部 Pendred 综合征存在奠基者突变的可能性。
在本研究中，我们对来自伊朗西北部的两个无血缘关系的家庭进行了全面的临床和基因评估，这两个家庭中有9名成员患有听力损失（HL）。在检测短串联重复序列（STR）标记以确认与SLC26A4位点的连锁关系后，我们通过对所有21个外显子、外显子-内含子边界以及启动子区域进行桑格测序，筛查SLC26A4基因是否存在任何致病突变。我们在这两个家庭中发现了与我们之前在另外两个来自伊朗西北部的阿塞拜疆家庭中检测到的相同致病突变。为了研究这四个家庭中存在奠基者效应的可能性，我们进行了单倍型分析，并对SLC26A4基因的14个单核苷酸多态性（SNP）进行了基因分型。
这两个家庭中的患者表现出 Pendred 综合征的表型。在这两个家庭中均发现了外显子8中一个已知的移码突变（c.965insA，p.N322Fs7X），这与我们之前在另外两个阿塞拜疆家庭中检测到的突变相同。单倍型分析结果显示，来自四个家庭的所有15名患者均共享该奠基者突变。在非携带者成员中未观察到常见单倍型。
基于我们两项研究的结果，c.965insA突变仅在来自伊朗西北部的伊朗家庭中被描述过，因此有证据表明该奠基者突变起源于伊朗的这一地区。
