GJB2单杂合突变非综合征型耳聋致病机制的研究
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摘要
目的：进行GJB2单杂合突变非综合征型耳聋（NSHI）患者的筛选，分析和总结GJB2单杂合突变患者的基因型与表型及其相互关系。探讨携带GJB2单杂合突变NSHI患者GJA1突变情况。探讨GJB2单杂合突变NSHI患者GJB2序列是否存在大片段碱基插入或缺失。
方法：第一部分对解放军总医院聋病分子诊断中心的7514例NSHI患者基因诊断的结果进行分析，筛选出GJB2单杂合突变而未查出其他常见耳聋基因突变（如GJB3、GJB6、SLC26A4、mtDNA等）的病例217例，分析GJB2单杂合致病突变类型以及单核苷酸多态（SNP），总结临床特点，包括一般资料、听力学结果和颞骨高分辨率CT（HRCT）。听力学检查包括：纯音测听及小儿行为测听191例、声导抗74例、听性脑干反应(ABR)60例、耳声发射(OAEs)47例、40Hz听觉事件相关电位(AERP)35例、听觉稳态反应(ASSR)29例。由于不是每个病例都做全上述检查，全国流行病学调查的病例仅有纯音测听，26例患者无法配合纯音测听但客观听力测试提示为感音神经性聋，因此每种检查的病例数不相同。第二部分对205例（12例无DNA标本）GJB2单杂合突变NSHI患者进行GJA1编码区直接测序，对照组为111例听力正常成年人。第三部分应用长链PCR及0.8%琼脂糖凝胶电泳检测201例（16例无DNA标本）GJB2单杂合突变NSHI患者GJB2全序列长度，对照组同第二部分。
结果：7514例NSHI中筛选出GJB2单杂合突变217例（2.89%，217/7514），男119例，女98例，共筛查出GJB2单杂合致病突变17种，最常见的突变类型为235delC杂合152例（70.05%）、299delAT杂合28例（12.90%）、176del16杂合6例（2.76%），其它突变类型31例（14.29%）。SNP分析：无SNP100例（46.08%），109G>A杂合53例（24.42%），79G>A杂合+341A>G杂合32例（14.75%），79G>A杂合24例（11.06%），其它类型SNP8例（3.69%）。191例纯音测听结果：极重度聋132例（69.11%），重度聋25例（13.09%），中度聋25例（13.09%），轻度聋7例（3.66%），正常2例（1.05%）；162例（162/191，84.82%）表现为双侧对称性听力下降，29例（15.18%）不对称；移码突变176例（92.14%，176/191），其中极重度聋123例（69.89%，123/176），错义突变13例（6.81%，13/191），无义突变2例（1.05%，2/191）。74例声导抗结果：鼓室压图为A型102耳（68.92%），As型27耳（18.24%），C型9耳（6.08%），Ad型6耳（4.05%），B型2耳（1.35%）和D型2耳（1.35%）；声反射阈：(80-95）dB HL37耳（25.00%），（96-110）dB HL18耳（12.16%），声发射未引出93耳（62.84%）；重振48耳（32.88%）。60例ABR结果：未引出反应63耳（52.50%），ABR阈值（30-60）dB nHL15耳（12.50%），（61-90）dB nHL23耳（19.17%），＞90dB nHL19耳（15.83%）。35例40Hz AERP结果：1kHz反应阈值≤60dB nHL5耳（7.14%），（61-90）dB nHL14耳（20.00%），（91-120）dB nHL35耳（50.00%），＞120dB nHL16耳（22.86%）。29例ASSR结果：ASSR反应阈值≤80HLcg8耳（13.79%），（81-119）HLcg38耳（65.52%），≥120HLcg12耳（20.69%）。47例OAEs结果：87耳（92.55%）OAEs无反应，7耳（7.45%）不同程度引出反应。95例颞骨CT检查发现内耳畸形3例（3.16%）。205例GJB2单杂合突变患者中，GJA1IVS2+1insA杂合突变3例（1.45%），456G>A和717G>A各1例，都为杂合同义突变。111例对照组中， IVS2+1insA杂合突变3例（2.70%），466A>G杂合突变1例(0.90%)。两组IVS2+1insA突变率无明显差异（校正χ2=0.115，P=0.735＞0.05）。201例GJB2单杂合突变患者和111例对照组GJB2序列长度检测均未见明显异常。
结论：中国GJB2单杂合突变NSHI患者常见的突变类型为235delC杂合、299delAT杂合和176del16杂合，以移码突变最常见，其基因型相关的听力表型多种多样，临床表现大多数为双侧对称性极重度语前聋，A型及As型鼓室压图常见，ABR、OAEs、40HzAERP、ASSR等是重要的检查方法，颞骨CT可见内耳畸形。GJB2单杂合突变NSHI患者中GJA1检测未见致病突变，GJB2序列长度检测未见明显异常，GJB2序列可能无大片段碱基插入或缺失。
Objective: To screen the nonsyndromic hearing impairment (NSHI) patientswith monoallelic mutations of the GJB2gene, and to summarize thecharacteristics of genotype and phenotype of monoallelic mutations of the GJB2gene and the genotype-phenotype correlation. To evaluate GJA1gene mutationsin NSHI patients with monoallelic GJB2mutations. To explore the underlyingpathogenic factors for the NSHI patients with monoallelic mutations of the GJB2gene, and to detect whether or not insertion or deletion of large fragmentnucleotides exists in the GJB2gene sequence.
Material and Methods: In part one, we analyzed the results of genediagnosis for7514NSHI patients from the Deafness Molecular DiagnosticsCenter of the People's Liberation Army General Hospital and chose217caseswith monoallelic mutations of the GJB2gene but without the other commondeafness gene mutations for further study, such as GJB3gene, GJB6gene,SLC26A4gene, mitochondria DNA, etc. We analyzed the genotype of the GJB2gene monoallelic mutations and the single nucleotide polymorphism(SNP) andsummarized the clinical characteristics of the patients with GJB2geneheterozygous mutations, including the general information of the patients, theaudiological results and the radiological imaging data. The appropriateaudiological tests were selected according to the patients' condition, includingpure tone audiometry, children behavioural audiometry, acoustic impedanceaudiometry, auditory brainstem response (ABR),40Hz auditory event related potentials(40Hz AERP), auditory steady-state response (ASSR), otoacousticemissions(OAEs), etc. In part two, we sequenced the entire coding region of theGJA1gene in205nonsyndromic hearing-impaired patients carrying a pathogenicGJB2gene mutation and in111normal hearing controls. In part three, wedetected the full length of the GJB2gene sequence for201NSHI patients withGJB2gene monoallelic mutations and111adults with normal hearing by longchain two-step PCR method and0.8%agarose gel electrophoresis(AGE).
Results: The monoallelic mutation rate of the GJB2gene was2.89%(217/7541) in the Chinese NSHI patients. Among the217NSHI patientswith monoallelic GJB2gene mutations, there are119males and98females. Therewere17types of monoallelic pathologic mutations of the GJB2gene, the mostcommon types of monoallelic mutations were235delC heterozygous,299delATheterozygous and176del16heterozygous, with152cases (70.05%),28cases(12.90%),6cases (2.76%), respectively. There were100cases(46.08%) withoutany SNP in the patients with monoallelic GJB2gene mutations,53cases (24.42%)only with heterozygous109G>A,32cases (14.75%) with heterozygous of79G>Aand341A>G,24cases（11.06%）only with heterozygous79G>A, and8cases(3.69%) with other types of heterozygous SNP. The results of pure toneaudiometry test for191cases were132cases (69.11%) with very severe hearingloss,25cases (13.09%) with severe hearing loss,25cases (13.09%) withmoderate hearing loss,7cases (3.66%) with mild hearing loss, and2cases (1.05%)with normal hearing; there were162cases (84.82%) with bilateral symmetricalhearing loss and29cases (15.18%) with binaural nonsymmetrical hearing loss.There were176patients (92.14%,176/191) with frameshift mutations,13patients(6.81%,13/191）with missense mutations and2patients (1.05%,2/191) withnonsense mutations, and123patients (69.89%,123/176）with very severe hearingloss and frameshift mutations. The results of acoustic impedance audiometry test for74cases were102ears (68.92%) with type A of tympanogram,27ears(18.24%) with type As,9ears (6.08%) with type C,6ears (4.05%) with type Ad,2ears (1.35%) with type B and2ears (1.35%) with type D; there were37ears(25.00%) with the acoustic reflex threshold less than or equal to95dB,18ears(12.16%) with the acoustic reflex threshold between96dB and110dB and93ears(62.84%) without acoustic reflex; there were48ears (32.88%) with recruitment.The results of ABR for66cases were63ears (52.50%) without response,15ears(12.50%) with the threshold of ABR between30dB nHL and60dB nHL,23ears(19.17%) with the threshold between61dB nHL and90dB nHL, and19ears(15.83%) with the threshold more than90dB nHL. The results of40Hz AERP for35cases were5ears (7.14%) with the threshold of40Hz AERP less than or equalto60dB nHL,14ears (20.00%) with the threshold between61dB nHL and90dBnHL,35ears (50.00%) with the threshold between91dB nHL and120dB nHL,and12ears (22.86%) without response more than120dB nHL. The threshold ofASSR was the average threshold at0.5、1、2、4kHz, and the results of ASSR for29cases were8ears (13.79%) with the threshold of ASSR less than or equal to80HLcg,38ears (65.52%) with the threshold between81HLcg and119HLcg,12ears (20.69%) with the threshold equal to or more than120HLcg. The results ofOAEs for47cases were87ears (92.55%) without OAEs response and only7earswith OAEs response. Three of95patients were found having malformations ininner ear by temporal bone HRCT. Five of the205patients were found havingmonoallelic GJA1gene mutations,3(1.45%) having IVS2+1insA mutations,1having456G>A mutation, and1having717G>A mutation. Four individuals fromthe control group were found having monoallelic GJA1gene mutations,3(2.70%)with IVS2+1insA mutations, and1with466A>G mutation. No significantdifference in the IVS2+1insA mutation rate was found between the two groups(continuity correction χ2=0.115, P=0.735＞0.05). Obvious increase or decrease of the sequence length of GJB2gene was not found in201NSHI patients withmonoallelic GJB2gene mutations and in the111cases from the control group.
Conclusion: The common types of monoallelic mutations of the GJB2genemonoallelic mutations in Chinese NSHI patients were235delC heterozygous,299delAT heterozygous and176del16heterozygous. The main clinicalmanifestation of most NSHI patients with monoallelic mutations of the GJB2gene showed bilateral, symmetrical, prelingual and very severe hearing loss. Thegenotype-phenotype correlation of monoallelic mutations of the GJB2generevealed versatility and polymorphism. The most common tympanogram typeswere type A and type As, and the patients whose acoustic reflection could beelicited often had recruitment. Other audiological tests were important means forNSHI patients, such as ABR, OAEs,40Hz AERP and ASSR. Malformations ofthe inner ear could be found in NSHI patients with monoallelic GJB2genemutations. Pathologic mutations of GJA1gene do not appear in NSHI patientswith monoallelic GJB2gene mutations. Insertion or deletion of large fragmentnucleotides in the GJB2gene sequence was not found in NSHI patients withmonoallelic GJB2gene mutations.
方法：第一部分对解放军总医院聋病分子诊断中心的7514例NSHI患者基因诊断的结果进行分析，筛选出GJB2单杂合突变而未查出其他常见耳聋基因突变（如GJB3、GJB6、SLC26A4、mtDNA等）的病例217例，分析GJB2单杂合致病突变类型以及单核苷酸多态（SNP），总结临床特点，包括一般资料、听力学结果和颞骨高分辨率CT（HRCT）。听力学检查包括：纯音测听及小儿行为测听191例、声导抗74例、听性脑干反应(ABR)60例、耳声发射(OAEs)47例、40Hz听觉事件相关电位(AERP)35例、听觉稳态反应(ASSR)29例。由于不是每个病例都做全上述检查，全国流行病学调查的病例仅有纯音测听，26例患者无法配合纯音测听但客观听力测试提示为感音神经性聋，因此每种检查的病例数不相同。第二部分对205例（12例无DNA标本）GJB2单杂合突变NSHI患者进行GJA1编码区直接测序，对照组为111例听力正常成年人。第三部分应用长链PCR及0.8%琼脂糖凝胶电泳检测201例（16例无DNA标本）GJB2单杂合突变NSHI患者GJB2全序列长度，对照组同第二部分。
结果：7514例NSHI中筛选出GJB2单杂合突变217例（2.89%，217/7514），男119例，女98例，共筛查出GJB2单杂合致病突变17种，最常见的突变类型为235delC杂合152例（70.05%）、299delAT杂合28例（12.90%）、176del16杂合6例（2.76%），其它突变类型31例（14.29%）。SNP分析：无SNP100例（46.08%），109G>A杂合53例（24.42%），79G>A杂合+341A>G杂合32例（14.75%），79G>A杂合24例（11.06%），其它类型SNP8例（3.69%）。191例纯音测听结果：极重度聋132例（69.11%），重度聋25例（13.09%），中度聋25例（13.09%），轻度聋7例（3.66%），正常2例（1.05%）；162例（162/191，84.82%）表现为双侧对称性听力下降，29例（15.18%）不对称；移码突变176例（92.14%，176/191），其中极重度聋123例（69.89%，123/176），错义突变13例（6.81%，13/191），无义突变2例（1.05%，2/191）。74例声导抗结果：鼓室压图为A型102耳（68.92%），As型27耳（18.24%），C型9耳（6.08%），Ad型6耳（4.05%），B型2耳（1.35%）和D型2耳（1.35%）；声反射阈：(80-95）dB HL37耳（25.00%），（96-110）dB HL18耳（12.16%），声发射未引出93耳（62.84%）；重振48耳（32.88%）。60例ABR结果：未引出反应63耳（52.50%），ABR阈值（30-60）dB nHL15耳（12.50%），（61-90）dB nHL23耳（19.17%），＞90dB nHL19耳（15.83%）。35例40Hz AERP结果：1kHz反应阈值≤60dB nHL5耳（7.14%），（61-90）dB nHL14耳（20.00%），（91-120）dB nHL35耳（50.00%），＞120dB nHL16耳（22.86%）。29例ASSR结果：ASSR反应阈值≤80HLcg8耳（13.79%），（81-119）HLcg38耳（65.52%），≥120HLcg12耳（20.69%）。47例OAEs结果：87耳（92.55%）OAEs无反应，7耳（7.45%）不同程度引出反应。95例颞骨CT检查发现内耳畸形3例（3.16%）。205例GJB2单杂合突变患者中，GJA1IVS2+1insA杂合突变3例（1.45%），456G>A和717G>A各1例，都为杂合同义突变。111例对照组中， IVS2+1insA杂合突变3例（2.70%），466A>G杂合突变1例(0.90%)。两组IVS2+1insA突变率无明显差异（校正χ2=0.115，P=0.735＞0.05）。201例GJB2单杂合突变患者和111例对照组GJB2序列长度检测均未见明显异常。
结论：中国GJB2单杂合突变NSHI患者常见的突变类型为235delC杂合、299delAT杂合和176del16杂合，以移码突变最常见，其基因型相关的听力表型多种多样，临床表现大多数为双侧对称性极重度语前聋，A型及As型鼓室压图常见，ABR、OAEs、40HzAERP、ASSR等是重要的检查方法，颞骨CT可见内耳畸形。GJB2单杂合突变NSHI患者中GJA1检测未见致病突变，GJB2序列长度检测未见明显异常，GJB2序列可能无大片段碱基插入或缺失。
Objective: To screen the nonsyndromic hearing impairment (NSHI) patientswith monoallelic mutations of the GJB2gene, and to summarize thecharacteristics of genotype and phenotype of monoallelic mutations of the GJB2gene and the genotype-phenotype correlation. To evaluate GJA1gene mutationsin NSHI patients with monoallelic GJB2mutations. To explore the underlyingpathogenic factors for the NSHI patients with monoallelic mutations of the GJB2gene, and to detect whether or not insertion or deletion of large fragmentnucleotides exists in the GJB2gene sequence.
Material and Methods: In part one, we analyzed the results of genediagnosis for7514NSHI patients from the Deafness Molecular DiagnosticsCenter of the People's Liberation Army General Hospital and chose217caseswith monoallelic mutations of the GJB2gene but without the other commondeafness gene mutations for further study, such as GJB3gene, GJB6gene,SLC26A4gene, mitochondria DNA, etc. We analyzed the genotype of the GJB2gene monoallelic mutations and the single nucleotide polymorphism(SNP) andsummarized the clinical characteristics of the patients with GJB2geneheterozygous mutations, including the general information of the patients, theaudiological results and the radiological imaging data. The appropriateaudiological tests were selected according to the patients' condition, includingpure tone audiometry, children behavioural audiometry, acoustic impedanceaudiometry, auditory brainstem response (ABR),40Hz auditory event related potentials(40Hz AERP), auditory steady-state response (ASSR), otoacousticemissions(OAEs), etc. In part two, we sequenced the entire coding region of theGJA1gene in205nonsyndromic hearing-impaired patients carrying a pathogenicGJB2gene mutation and in111normal hearing controls. In part three, wedetected the full length of the GJB2gene sequence for201NSHI patients withGJB2gene monoallelic mutations and111adults with normal hearing by longchain two-step PCR method and0.8%agarose gel electrophoresis(AGE).
Results: The monoallelic mutation rate of the GJB2gene was2.89%(217/7541) in the Chinese NSHI patients. Among the217NSHI patientswith monoallelic GJB2gene mutations, there are119males and98females. Therewere17types of monoallelic pathologic mutations of the GJB2gene, the mostcommon types of monoallelic mutations were235delC heterozygous,299delATheterozygous and176del16heterozygous, with152cases (70.05%),28cases(12.90%),6cases (2.76%), respectively. There were100cases(46.08%) withoutany SNP in the patients with monoallelic GJB2gene mutations,53cases (24.42%)only with heterozygous109G>A,32cases (14.75%) with heterozygous of79G>Aand341A>G,24cases（11.06%）only with heterozygous79G>A, and8cases(3.69%) with other types of heterozygous SNP. The results of pure toneaudiometry test for191cases were132cases (69.11%) with very severe hearingloss,25cases (13.09%) with severe hearing loss,25cases (13.09%) withmoderate hearing loss,7cases (3.66%) with mild hearing loss, and2cases (1.05%)with normal hearing; there were162cases (84.82%) with bilateral symmetricalhearing loss and29cases (15.18%) with binaural nonsymmetrical hearing loss.There were176patients (92.14%,176/191) with frameshift mutations,13patients(6.81%,13/191）with missense mutations and2patients (1.05%,2/191) withnonsense mutations, and123patients (69.89%,123/176）with very severe hearingloss and frameshift mutations. The results of acoustic impedance audiometry test for74cases were102ears (68.92%) with type A of tympanogram,27ears(18.24%) with type As,9ears (6.08%) with type C,6ears (4.05%) with type Ad,2ears (1.35%) with type B and2ears (1.35%) with type D; there were37ears(25.00%) with the acoustic reflex threshold less than or equal to95dB,18ears(12.16%) with the acoustic reflex threshold between96dB and110dB and93ears(62.84%) without acoustic reflex; there were48ears (32.88%) with recruitment.The results of ABR for66cases were63ears (52.50%) without response,15ears(12.50%) with the threshold of ABR between30dB nHL and60dB nHL,23ears(19.17%) with the threshold between61dB nHL and90dB nHL, and19ears(15.83%) with the threshold more than90dB nHL. The results of40Hz AERP for35cases were5ears (7.14%) with the threshold of40Hz AERP less than or equalto60dB nHL,14ears (20.00%) with the threshold between61dB nHL and90dBnHL,35ears (50.00%) with the threshold between91dB nHL and120dB nHL,and12ears (22.86%) without response more than120dB nHL. The threshold ofASSR was the average threshold at0.5、1、2、4kHz, and the results of ASSR for29cases were8ears (13.79%) with the threshold of ASSR less than or equal to80HLcg,38ears (65.52%) with the threshold between81HLcg and119HLcg,12ears (20.69%) with the threshold equal to or more than120HLcg. The results ofOAEs for47cases were87ears (92.55%) without OAEs response and only7earswith OAEs response. Three of95patients were found having malformations ininner ear by temporal bone HRCT. Five of the205patients were found havingmonoallelic GJA1gene mutations,3(1.45%) having IVS2+1insA mutations,1having456G>A mutation, and1having717G>A mutation. Four individuals fromthe control group were found having monoallelic GJA1gene mutations,3(2.70%)with IVS2+1insA mutations, and1with466A>G mutation. No significantdifference in the IVS2+1insA mutation rate was found between the two groups(continuity correction χ2=0.115, P=0.735＞0.05). Obvious increase or decrease of the sequence length of GJB2gene was not found in201NSHI patients withmonoallelic GJB2gene mutations and in the111cases from the control group.
Conclusion: The common types of monoallelic mutations of the GJB2genemonoallelic mutations in Chinese NSHI patients were235delC heterozygous,299delAT heterozygous and176del16heterozygous. The main clinicalmanifestation of most NSHI patients with monoallelic mutations of the GJB2gene showed bilateral, symmetrical, prelingual and very severe hearing loss. Thegenotype-phenotype correlation of monoallelic mutations of the GJB2generevealed versatility and polymorphism. The most common tympanogram typeswere type A and type As, and the patients whose acoustic reflection could beelicited often had recruitment. Other audiological tests were important means forNSHI patients, such as ABR, OAEs,40Hz AERP and ASSR. Malformations ofthe inner ear could be found in NSHI patients with monoallelic GJB2genemutations. Pathologic mutations of GJA1gene do not appear in NSHI patientswith monoallelic GJB2gene mutations. Insertion or deletion of large fragmentnucleotides in the GJB2gene sequence was not found in NSHI patients withmonoallelic GJB2gene mutations.
引文
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