大前庭水管综合征相关基因突变检测及功能研究
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摘要
目的:
大前庭水管综合征(large vestibular aqueduct syndrome,LVAS或enlarged vestibular aqueduct syndrome,EVAS)是以前庭导水管扩大伴有感音神经性聋(SNHL)为特征的一种常染色体隐性遗传性非综合征型听力障碍性疾病。为了系列研究EVAS的临床特征、基因突变检测、基因功能,我们对19例EVAS患者的临床、听力学及影像学特征进行分析;对相关基因SLC26A4、FOXI1行突变检测,发现特异和常见的突变图谱;通过构建突变体转染HEK293T细胞,观察SLC26A4基因突变对其编码的Pendrin蛋白的表达定位产生的影响,从而为进一步研究该基因突变的致病机理打下基础。
方法:
选择年长配合儿童及成人行纯音测听(PTA)检查,对不能主动配合纯音测听的幼儿,用声场行为听阈测试(BA);所有患者行听性脑干反应(ABR)和40Hz相关电位(40 AERP)测试、声导抗及耳声发射检查;ABR在最大给声无反应的患者,增加听觉稳态反应(ASSR)了解患者的残余听力。完成CT及MRI检查。
应用聚合酶链反应(PCR)结合DNA直接测序方法,用DNASTAR软件中的EditSeq、SeqMan程序分析,对19例EVAS患者的SLC26A4基因的21个外显子、FOXI1的2个外显子及相邻的内含子区域进行突变检测和分析。
将野生型、突变型SLC26A4连入真核表达载体pEGFP-N1中,与EGFP构成融合蛋白,转染HEK293T细胞,Western Blot检测蛋白表达;免疫荧光观察细胞定位,激光共聚焦显微镜拍照。
结果:
1.EVAS的典型表现是儿童时期的听力丧失,主要为SNHL,听力下降呈进行性或波动性,双耳受累者多见。听力水平多为中重度耳聋以上。听力受损以高频为主,听力曲线多呈下降型。特有的听力学表现即低频骨气导差及声诱发短潜伏期负反应ASNR在本组研究中分别占44.1%和42.1%。影像学检查是诊断的金标准,行人工耳蜗植入易出现“镫井喷”,但恰当处理不影响耳蜗植入。
2.19例患者17例检出SLC26A4基因突变,突变率高达84.2%。12例为复合杂合突变,3例为纯合突变,2例杂合突变,2例无突变。共查及17种不同类型的SLC26A4基因的致病突变,13种为错义突变,2种剪接位点突变,1种无义突变和1种大片段缺失。其中16种为国内外已报道的突变,IVS7-2A＞G最多见,占34.4%。1种新发突变1716A＞T/F572L。对FOXI1基因检测发现两个多态:279 G＞A,1044T＞C。
3.成功构建SLC26A4基因的野生型和S448X突变体pEGFPN1融合表达载体,命名为pEGFP N1 PDS WT和pEGFP N1 PDS S448X;并成功转染HEK293T细胞,Western blot检测PDS WT和PDS S448X蛋白的表达正确。免疫荧光染色和激光共聚焦显微镜下发现S448X突变体绿色荧光局限在胞质,细胞膜没有清晰的绿色荧光显示。而大部分野生型细胞膜上有清晰的绿色荧光显示。
结论:
1.EVAS是以前庭导水管扩大伴有感音神经性聋(SNHL)为特征的一种隐性遗传性非综合征型听力障碍性疾病。临床听力学存在特征性改变,如低频骨气导差及声诱发短潜伏期负反应有助于发现该疾病,但诊断的金标准仍是影像学。行人工耳蜗植入易出现“镫井喷”,但恰当处理不影响耳蜗植入。
2.本组EVAS患者,SLC26A4基因的突变率高达84.2%,说明SLC26A4基因突变与EVAS密切相关,同时提示如果我们在进行听力损失患者的基因筛查中首先发现SLC26A4基因突变,则高度预示该患者为EVAS患者,从基因检测中发现临床疾病。新发突变1716A＞T/F572L进一步丰富了中国人群的突变图谱,可以利用中国人IVS7-2A＞G的热点突变开展快速筛查工作。FOXI1作为SLC26A4的转录调控因子不是唯一的,EVAS的发生可能存在其他的致病因素。
3.SLC26A4基因的S448X的突变,使突变蛋白局限于胞质,不能准确定位在细胞膜上。
Objective:
Large vestibular aqueduct syndrome(LVAS) or enlarged vestibular aqueduct syndrome(EVAS) is an autosomal recessive nonsyndromic hearing loss which is characterized as enlarged vestibular aqueduct and Sensorineural hearing loss(SNHL). To study its clinical features、genetic mutation and gene function systematically, We analyzed the serial characters of clinic、audiometry and imageology of 19 EVAS patients, carried gene mutation detections on SLC26A4 and FOXI1 to find specific and frequent mutation map, constructed mutant and transfected HEK293T cell to observe the influence of gene mutation on Pendrin' s expression to study the pathopoiesis mechanism of SLC26A4 gene mutation.
Methods:
The audiometry included pure tone audiometry(PTA) or behavior audiometry(BA), acoustic immitance (tympanometry, acoustic reflex thresholds and stapedius muscle reflex), otoacoustic emissions (OAE), auditory brain stem responses (ABR), 40Hz auditory event related potential(40Hz AERP), auditory steady-state response (ASSR). Different tests were chosen according to different ages and circumstances to get the audiological datas. Computed tomography scan(CT) of the temporal bone and magnetic resonance imaging(MRI) were used for understanding the structure of cochlea and endolymphatic sac. All above methods were used in clinic.
Mutation analysis was carried out by the method of polymerase chain reaction(PCR) and direct sequencing on 21 exons of SLC26A4 gene and 2 exons of FOXI1 gene and their consecutive part of introns. Then we used the software of DNAStar (EditSeq and SeqMan) to analyze the sequence.
Mutant and wild type of PDS were reconstructed with pEGFP-N1 expression vector and transfected HEK293T cell. By the method of western blot and immunofluorescence , we tested the expression protein and got the photo through Confocal microscopy.
Results:
1. The classic performance of EVAS is bilateral hearing loss, especially SNHL with character of progressive or fluctuate hearing loss in childhood. The majority is worse than moderate severe hearing loss with decreasing in high frequency. Air-bone gap and ASNR account for 44.1 % and 42.1% , which are the characters of EVAS. While the imageology is the golden standard of diagnosis of EVAS. Stapedial gusher always happened in cochlear implantation, while otologists should carefully deal with it to get a good result.
2. There were 17 EVAS patients who had SLC26A4 gene mutations in 19 EVAS patients. The mutation rate reached up to 84.2%. 12 were complex heterozygosis mutations, 3 were homozygosis mutations, 2 were heterozygosis mutations and there were no mutations in the 2 patients left. 17 different pathopoiesis mutations of SLC26A4 gene were detected. Among these mutations, 13 were missense mutations, 2 were splicing site mutations, 1 was nonsense mutation and the other 1 was klenow fragment deletion. 16 mutations have been reported before, IVS7-2A>G was at most, which accounted 34.4%. While a novel mutation 1716A>T /F572L was found in this examination. There were 2 polymorphisms of FOXI1 in 19 EVAS patients: 279 G>A、1044T>C.
3. We successfully constructed SLC26A4 gene wild-type and S448X mutant green fluorescent vectors. They were named as pEGFP N1 PDS WT and pEGFP N1 PDS S448X. HEK293T cells were successfully transfected with pEGFP N1 PDS WT and pEGFP N1 PDS S448X. The expression of PDS WT and PDS S448X protein were detected by the method of western blot. With the help of immunofluorescence staining and laser Confocal microscopy, we founded that pEGFP N1 PDS S448X was limited in cytoplasm, there wasn't limpid green fluorescence on cytomembrane. while the majority of pEGFP N1 PDS WT has clear green fluorescence on cytomembrane.
Conclusions:
1. EVAS is an autosomal recessive nonsyndromic hearing loss which is characterized as enlarged vestibular aqueduct and Sensorineural hearing loss(SNHL). Characteristics of audiology such as air-bone gap at low frequency and acoustically evoked short latency negative response(ASNR) can help us to discover this disease. The golden standard of EVAS is imageology. Stapedial gusher always happened in cochlear implantation, while otologists should carefully deal with it to get a good result.
2. In this study, the mutation rate of SLC26A4 reached up to 84.2%. This data demonstrated that SLC26A4 gene mutation had close correlation with EVAS. Since gene mutation can prognosticate EVAS, then clinic disease can be found by gene detection. The novel mutation 1716A>T /F572L multiplied Chinese mutation map. We can use the hot spot mutation IVS7-2A>G to develop fast screening of SLC26A4. FOXI1 was not the unique transcriptional control factor of SLC26A4. Other etiological factors maybe exist in the development of EVAS.
3. The mutation of S448X of SLC26A4 gene caused the result that mutein was limited in cytoplasm, it couldn't locate at cytomembrane correctly.
大前庭水管综合征(large vestibular aqueduct syndrome,LVAS或enlarged vestibular aqueduct syndrome,EVAS)是以前庭导水管扩大伴有感音神经性聋(SNHL)为特征的一种常染色体隐性遗传性非综合征型听力障碍性疾病。为了系列研究EVAS的临床特征、基因突变检测、基因功能,我们对19例EVAS患者的临床、听力学及影像学特征进行分析;对相关基因SLC26A4、FOXI1行突变检测,发现特异和常见的突变图谱;通过构建突变体转染HEK293T细胞,观察SLC26A4基因突变对其编码的Pendrin蛋白的表达定位产生的影响,从而为进一步研究该基因突变的致病机理打下基础。
方法:
选择年长配合儿童及成人行纯音测听(PTA)检查,对不能主动配合纯音测听的幼儿,用声场行为听阈测试(BA);所有患者行听性脑干反应(ABR)和40Hz相关电位(40 AERP)测试、声导抗及耳声发射检查;ABR在最大给声无反应的患者,增加听觉稳态反应(ASSR)了解患者的残余听力。完成CT及MRI检查。
应用聚合酶链反应(PCR)结合DNA直接测序方法,用DNASTAR软件中的EditSeq、SeqMan程序分析,对19例EVAS患者的SLC26A4基因的21个外显子、FOXI1的2个外显子及相邻的内含子区域进行突变检测和分析。
将野生型、突变型SLC26A4连入真核表达载体pEGFP-N1中,与EGFP构成融合蛋白,转染HEK293T细胞,Western Blot检测蛋白表达;免疫荧光观察细胞定位,激光共聚焦显微镜拍照。
结果:
1.EVAS的典型表现是儿童时期的听力丧失,主要为SNHL,听力下降呈进行性或波动性,双耳受累者多见。听力水平多为中重度耳聋以上。听力受损以高频为主,听力曲线多呈下降型。特有的听力学表现即低频骨气导差及声诱发短潜伏期负反应ASNR在本组研究中分别占44.1%和42.1%。影像学检查是诊断的金标准,行人工耳蜗植入易出现“镫井喷”,但恰当处理不影响耳蜗植入。
2.19例患者17例检出SLC26A4基因突变,突变率高达84.2%。12例为复合杂合突变,3例为纯合突变,2例杂合突变,2例无突变。共查及17种不同类型的SLC26A4基因的致病突变,13种为错义突变,2种剪接位点突变,1种无义突变和1种大片段缺失。其中16种为国内外已报道的突变,IVS7-2A＞G最多见,占34.4%。1种新发突变1716A＞T/F572L。对FOXI1基因检测发现两个多态:279 G＞A,1044T＞C。
3.成功构建SLC26A4基因的野生型和S448X突变体pEGFPN1融合表达载体,命名为pEGFP N1 PDS WT和pEGFP N1 PDS S448X;并成功转染HEK293T细胞,Western blot检测PDS WT和PDS S448X蛋白的表达正确。免疫荧光染色和激光共聚焦显微镜下发现S448X突变体绿色荧光局限在胞质,细胞膜没有清晰的绿色荧光显示。而大部分野生型细胞膜上有清晰的绿色荧光显示。
结论:
1.EVAS是以前庭导水管扩大伴有感音神经性聋(SNHL)为特征的一种隐性遗传性非综合征型听力障碍性疾病。临床听力学存在特征性改变,如低频骨气导差及声诱发短潜伏期负反应有助于发现该疾病,但诊断的金标准仍是影像学。行人工耳蜗植入易出现“镫井喷”,但恰当处理不影响耳蜗植入。
2.本组EVAS患者,SLC26A4基因的突变率高达84.2%,说明SLC26A4基因突变与EVAS密切相关,同时提示如果我们在进行听力损失患者的基因筛查中首先发现SLC26A4基因突变,则高度预示该患者为EVAS患者,从基因检测中发现临床疾病。新发突变1716A＞T/F572L进一步丰富了中国人群的突变图谱,可以利用中国人IVS7-2A＞G的热点突变开展快速筛查工作。FOXI1作为SLC26A4的转录调控因子不是唯一的,EVAS的发生可能存在其他的致病因素。
3.SLC26A4基因的S448X的突变,使突变蛋白局限于胞质,不能准确定位在细胞膜上。
Objective:
Large vestibular aqueduct syndrome(LVAS) or enlarged vestibular aqueduct syndrome(EVAS) is an autosomal recessive nonsyndromic hearing loss which is characterized as enlarged vestibular aqueduct and Sensorineural hearing loss(SNHL). To study its clinical features、genetic mutation and gene function systematically, We analyzed the serial characters of clinic、audiometry and imageology of 19 EVAS patients, carried gene mutation detections on SLC26A4 and FOXI1 to find specific and frequent mutation map, constructed mutant and transfected HEK293T cell to observe the influence of gene mutation on Pendrin' s expression to study the pathopoiesis mechanism of SLC26A4 gene mutation.
Methods:
The audiometry included pure tone audiometry(PTA) or behavior audiometry(BA), acoustic immitance (tympanometry, acoustic reflex thresholds and stapedius muscle reflex), otoacoustic emissions (OAE), auditory brain stem responses (ABR), 40Hz auditory event related potential(40Hz AERP), auditory steady-state response (ASSR). Different tests were chosen according to different ages and circumstances to get the audiological datas. Computed tomography scan(CT) of the temporal bone and magnetic resonance imaging(MRI) were used for understanding the structure of cochlea and endolymphatic sac. All above methods were used in clinic.
Mutation analysis was carried out by the method of polymerase chain reaction(PCR) and direct sequencing on 21 exons of SLC26A4 gene and 2 exons of FOXI1 gene and their consecutive part of introns. Then we used the software of DNAStar (EditSeq and SeqMan) to analyze the sequence.
Mutant and wild type of PDS were reconstructed with pEGFP-N1 expression vector and transfected HEK293T cell. By the method of western blot and immunofluorescence , we tested the expression protein and got the photo through Confocal microscopy.
Results:
1. The classic performance of EVAS is bilateral hearing loss, especially SNHL with character of progressive or fluctuate hearing loss in childhood. The majority is worse than moderate severe hearing loss with decreasing in high frequency. Air-bone gap and ASNR account for 44.1 % and 42.1% , which are the characters of EVAS. While the imageology is the golden standard of diagnosis of EVAS. Stapedial gusher always happened in cochlear implantation, while otologists should carefully deal with it to get a good result.
2. There were 17 EVAS patients who had SLC26A4 gene mutations in 19 EVAS patients. The mutation rate reached up to 84.2%. 12 were complex heterozygosis mutations, 3 were homozygosis mutations, 2 were heterozygosis mutations and there were no mutations in the 2 patients left. 17 different pathopoiesis mutations of SLC26A4 gene were detected. Among these mutations, 13 were missense mutations, 2 were splicing site mutations, 1 was nonsense mutation and the other 1 was klenow fragment deletion. 16 mutations have been reported before, IVS7-2A>G was at most, which accounted 34.4%. While a novel mutation 1716A>T /F572L was found in this examination. There were 2 polymorphisms of FOXI1 in 19 EVAS patients: 279 G>A、1044T>C.
3. We successfully constructed SLC26A4 gene wild-type and S448X mutant green fluorescent vectors. They were named as pEGFP N1 PDS WT and pEGFP N1 PDS S448X. HEK293T cells were successfully transfected with pEGFP N1 PDS WT and pEGFP N1 PDS S448X. The expression of PDS WT and PDS S448X protein were detected by the method of western blot. With the help of immunofluorescence staining and laser Confocal microscopy, we founded that pEGFP N1 PDS S448X was limited in cytoplasm, there wasn't limpid green fluorescence on cytomembrane. while the majority of pEGFP N1 PDS WT has clear green fluorescence on cytomembrane.
Conclusions:
1. EVAS is an autosomal recessive nonsyndromic hearing loss which is characterized as enlarged vestibular aqueduct and Sensorineural hearing loss(SNHL). Characteristics of audiology such as air-bone gap at low frequency and acoustically evoked short latency negative response(ASNR) can help us to discover this disease. The golden standard of EVAS is imageology. Stapedial gusher always happened in cochlear implantation, while otologists should carefully deal with it to get a good result.
2. In this study, the mutation rate of SLC26A4 reached up to 84.2%. This data demonstrated that SLC26A4 gene mutation had close correlation with EVAS. Since gene mutation can prognosticate EVAS, then clinic disease can be found by gene detection. The novel mutation 1716A>T /F572L multiplied Chinese mutation map. We can use the hot spot mutation IVS7-2A>G to develop fast screening of SLC26A4. FOXI1 was not the unique transcriptional control factor of SLC26A4. Other etiological factors maybe exist in the development of EVAS.
3. The mutation of S448X of SLC26A4 gene caused the result that mutein was limited in cytoplasm, it couldn't locate at cytomembrane correctly.
引文
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