Waardenburg综合征和非综合征型耳聋的分子遗传学研究
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摘要
随着分子生物学和基因组学的发展,在基因水平上对耳聋病因学的诠释成为当今探究遗传性聋发病原因的热点。人们发现中国绝大部分遗传性非综合征型耳聋(NSHL)患者是由GJB2,SLC26A4和线粒体DNA基因突变导致,利用基因诊断技术对这三种基因进行突变检侧,不仅可为大部分遗传性耳聋患者明确病因,而且为耳聋遗传咨询提供了理论依据及科学手段,同时使对于遗传性耳聋家庭的产前诊断成为可能。目前,国内大部分地区已开展了上述基因突变的分子流行病学调查,但尚未在湖南地区进行相关的研究。
同时,综合征型耳聋的病因学研究也取得了很大的进展。Waardenburg综合征(WS)是最常见的综合征型耳聋之一。至今,欧美人群已发现100余种WS相关基因突变位点,逐渐从分子水平上揭示这种遗传性疾病的致病机制。但国内仅见少数WS病例的报道,有关中国人群WS患者的分子遗传背景的研究甚少。
本研究的主要目的是通过对SHL、NSHL和母系遗传的遗传性耳聋患者较系统的临床特征和分子遗传学研究,分析中国人群WS患者的分子遗传背景,探讨基因型-表型之间的相关性;了解湖南地区汉族非综合征型耳聋患者中GJB2和PDS基因的突变频率和突变热点,调查线粒体DNA 12SrRNAA1555G突变的流行频率,试图揭示这些基因与耳聋发生的紧密联系,探讨耳聋预防的策略和科学有效的治疗途径;并为一遗传性耳聋大家系明确分子病因,进而探讨mtDNA突变同非综合征型耳聋之间的关系。本研究主要包括以下三个部分:
第一章:Waardenburg综合征的临床特征及相关基因突变研究
我们对来自中南地区的19例Waardenburg综合征患者进行了临床诊断和分型,对其中5例WS1进行PAX3基因突变检测,另14例WS2进行MITF、SNAI2和SOX10基因突变检测。结果发现WS患者临床表型变异很大。所有患者均有虹膜异色;89.5%的患者表现为双侧对称的先天性极重度感音神经性耳聋,且以WS2中多见;同时,4例WS2(28.6%)表现为全身皮肤棕褐色雀斑沉着,其它症状如白额发、早白发等仅见于个别病例。共在16例WS中发现10种基因突变位点(PAX3和MITF基因各3种,SOX10基因4种),另3例突变检测阴性。所有WS1均携带PAX3基因突变,35.7%和42.9%的WS2患者分别检测到MITF和SOX10基因突变;其中8种(PAX3:H80D和H186fs;MITF:R217I和T192fs;SOX10:G38fs、R43X、E248fs和G37fs)为未报道新突变。为绘制中国人群WS相关基因突变图谱提供了重要的数据,并为揭示WS的分子致病机制打下了基础。
第二章:非综合征型耳聋常见耳聋相关基因的突变研究
我们采用直接测序、DHPLC和PCR-RFLP的方法对湖南地区汉族139例非综合征型耳聋患者分别进行GJB2、PDS和线粒体DNA12SrRNA A1555G突变的筛查,结果发现43.9%(61例)的患者至少携带其中一种基因突变;GJB2、PDS和线粒体DNA 12SrRNAA1555G突变的检出率分别为23%、18.7%和3.6%;共发现6种GJB2和13种PDS基因致病性突变,其中1种GJB2基因新突变(F115C)和3种PDS基因新突变(S8X、A227P和Cys565fs):235delC和IVS7-2A>G分别是GJB2和PDS基因最常见的突变类型,分别占这两个基因突变的89.1%和46.5%;通过此次筛查,为其中35.3%的患者明确了分子病因,为该地区进一步开展遗传咨询、基因诊断和产前诊断提供了重要的依据,并为临床用药提供指导。
第三章:一母系遗传非综合征型耳聋大家系的临床特征和分子病因学研究
我们对一母系遗传性耳聋大家系的临床特征进行归纳总结,并采用直接测序法对先证者进行线粒体全基因组序列分析,结果发现此家系内58.3%(21/36)的母系成员均表现为双侧对称、以高频下降明显的感音神经性耳聋,但发病年龄和耳聋的严重程度变异很大;氨基糖甙类抗生素与该家系部分成员的耳聋关系密切。序列分析共发现23种变异,其中T1541C为新突变。18例母系成员均同时携带12SrRNAA1555G和T1541C同质性突变。5例父系亲属及配偶听力正常,1555和1541位点突变检测阴性。
本研究最后得到以下结论:
(1)Waardenburg综合征临床表型变异很大,以WS2较多见;虹膜异色和感音神经性耳聋为WS最常见的症状;棕褐色雀斑沉着可能是中国人群WS患者皮肤色素改变的一种特殊的形式;PAX3基因突变是导致WS1患者致病的主要原因,而WS2中MITF和SOX10基因突变较欧美人群有更高的检出率,且SOX10基因突变更常见。研究发现10种基因突变位点,其中8种为新突变,表现出中国人群WS患者独特的基因突变谱。3例突变检测阴性提示可能存在其它未知的WS2致病基因。
(2)湖南地区汉族人群三项常见耳聋基因的筛查提示有43.9%的患者携带有常见耳聋基因突变,反映湖南地区遗传性聋高发的现象。GJB2基因突变是导致该地区汉族NSHL最常见的原因,其次为SLC26A4基因。235delC、IVS7-2A>G和A1555G突变分别是GJB2、PDS和线粒体DNA基因的热点突变,占所有突变的71.2%,可利用热点突变进一步开展快速筛查工作。通过本研究为其中35.3%的患者明确了病因。研究发现的1种GJB2和3种PDS基因新突变,进一步丰富了中国人群的耳聋基因突变谱。
(3)母系遗传性非综合征型耳聋主要表现为双侧对称、以高频下降明显的感音神经性耳聋,但发病年龄和耳聋的严重程度变异很大。mtDNA 12SrRNA A1555G突变是该家系耳聋的主要分子基础;环境因素和核基因可能参与A1555G突变表型表达的调节;T1541C为未报道新突变,可能对该家系A1555G突变所致耳聋的外显率有影响。
With the development of molecular biology and genomics,it's a research hotspot to explore the causes of hereditary deafness at the genetic level.Since the majority of Chinese hereditary deaf people had been confirmed to be caused by GJB2,SLC26A4 and mtDNA gene mutations,genetic testing of these three genes can not only make clear about cause of deafness but also provide theoretical evidences for genetic counseling.Furthermore,it makes prenatal diagnosis possible for deaf families.Now,many provinces has investigated the molecular epidemiology of the common deafness genes including GJB2,SLC26A4 and mtDNA A1555G mutations.But no similar research has been carried out in Hunan province.
Meanwhile,there has been remarkable progress being made on syndromic hearing loss.Waardenburg syndrome is one of the most common dieases of SHL.So far,more than 100 gene mutations have been reported in Western WS patients,which disclosed its possible molecular mechanisms.But few WS patients had been reported in China,and very few reports had been observed on the molecular genetic background of WS in Chinese population.
The purpose of the present study,through systematic study on clinical features and molecular genetics of patients with SHU、NSHL or maternally inherited nonsyndromic deafness,is to explore the molecular genetic background and relationship between genotype and phenotype of WS in Chinese population;To investigate the prevalence and hot spots of GJB2 and PDS genes and to estimate the incidence of the mitochondrial 12S ribosomal RNA A1555G mutation in subjects with NSHL in Han people of Hunan province,and try to disclose the mechanism of deafness associated with these genes and provide some theories or suggestions for preventing and curing this kind of hearing loss;Also to study the molecular etiology of a large family with maternally inherited nonsyndromic deafness and then to explore the relationship between mtDNA gene mutations and NSHL.We carried out our research as the following three parts:
Part one:The clinical features and gene mutations in patients with Waardenburg syndrome.
We analyzed the clinical features of 19 WS patients came from central south in China,in which 5 were diagonosed as WS type 1,while other 14 were WS type 2.All the WS1 patients were screened mutations for PAX3 gene and WS2 for MITF,SNAI2 and SOX10 gene mutations.We observed obvious phenotypic variability in Chinese WS patients.All the patients showed heterochromia iridis,and 89.5%patients displayed bilateral, congenital sensorineural hearing loss which was more common in WS2. We also observed 4 WS2 patients(28.6%) manifested much brown freckles on the skin,while other symptoms such as white forelock and premature greying could only be seen on a few patients.At molecular level,totally 10 mutations(3 mutations in PAX3 and MITF genes respectively,and 4 in SOX10) were identified and 8(H80D and H186fs in PAX3,R217I and T192fs in MITF,G38fs,R43X,E248fs and G37fs in SOX10) of them were novel.All the WS1 patients carried PAX3 gene mutations,while 35.7% and 42.9%of WS2 cases were detected MITF and SOX 10 gene mutations respectively.These results have provided important data to depicted the mutational spectrum in Chinese WS and the starting point to discover the underlying molecular mechanism of the disease.
Part two:Mutation analysis of common deafness genes in non syndromic hearing loss patients.
We carried out mutation screening of GJB2,PDS genes and mtDNA A1555G for 139 patients with NSHL in Han people of Hunan province by direct seqence,DHPLC and PCR-RFLP respectively.The study showed 43.9%patients carried at least one of the common genes mutations.The mutation detection rate of GJB2,PDS genes and mtDNA A1555G were 23%,18.7%and 3.6%respectively.Totatlly 6 GJB2 and 13 PDS gene mutations were identified,among them 1 GJB2(F115C) and 3 PDS(S8X, A227P,Cys565fs) gene mutations were novel.89.1%of GJB2 gene mutations was 235delC and 46.5%of PDS was IVS7-2A＞G,which implied 235delC and IVS7 -2A＞G were the most common mutations in the two genes.We made clear about the molecular etiology of 35.3%patients through this study,which supplied important data for further step to genetic counseling,gene diagnosis and prenatal diagnosis and also supplied instructions for clinical medication.
Part three:Clinical characterization and molecular genetic study of a large family with maternally inherited non-syndromic deafness.
We evaluated the clinical features of a large family with maternally inherited nonsyndromic deafness,and carried sequence analysis of the mitochondrial genome from the proband.The results showed 21 of 36 maternal members(58.3%) exhibited symmetric bilateral sensorineural hearing loss especially in high frequency,with a wide range of severity and ages at onset.Deafness of some maternal members was closely related to aminoglycoside antibiotic.Totally 23 variations were found by molecular analysis in the proband.18 maternal relatives harbored the homoplasmic mutation A1555G in thel2SrRNA gene,also a novel mutation T1541C.5 spouses and paternal relatives had nomal hearing and were negative of A1555G and T1541C mutations.
Conclusions:
(1) There are obvious variations in clinical features of WS,WS2 is more common than WS1;Heterochromia iridis and sensorineural hearing loss are the most common symptoms,while brown freckles may be a special type of pigmentary disturbance of the skin.Genetically,PAX3 mutations are mainly associated with WS1.The mutation detection rate of MITF and SOX10 genes in Chinese WS2 patients are higher than in European population,and SOX10 gene mutations are more common than MITF.Totally 10 different gene mutations were identified and 8 of them are novel,which implies the unique mutational spectrum in Chinese WS. No mutations were found in 3 WS2 patients,which means some other unknown genes related to WS2.
(2) There are about 43.9%patients with NSHL carried the common deafness gene mutations,which indicates high incidence of hereditary deafness in Han people of Hunan province.GJB2 gene mutations are the most common cause of NSHL,then PDS gene mutations.235delC, IVS7-2A＞G and A1555G are the hot spots in GJB2,PDS and mtDNA genes mutations respectively,which account for 71.2%of all three gene mutations.We can use the hot spot mutations to develop fast screening for the common deafness genes.The etiology of 35.3%patients in this study have been determined.1 GJB2 and 3 PDS novel gene mutations multiplied Chinese mutation map.
(3) The chacterization of maternally inherited nonsyndromic deafness is mainly symmetric bilateral sensorineural hearing loss especially in high frequency,with a wide range of severity and ages at onset.Mitochondrial mutation A1555G is mainly responsible for the disorder in this family. Environmental determinants and nuclear background may play a role in the clinical expression of deafness,T1541C is a novel mutation in Chinese population,and it may influence the penetrance of deafness due to A1555G mutation.
同时,综合征型耳聋的病因学研究也取得了很大的进展。Waardenburg综合征(WS)是最常见的综合征型耳聋之一。至今,欧美人群已发现100余种WS相关基因突变位点,逐渐从分子水平上揭示这种遗传性疾病的致病机制。但国内仅见少数WS病例的报道,有关中国人群WS患者的分子遗传背景的研究甚少。
本研究的主要目的是通过对SHL、NSHL和母系遗传的遗传性耳聋患者较系统的临床特征和分子遗传学研究,分析中国人群WS患者的分子遗传背景,探讨基因型-表型之间的相关性;了解湖南地区汉族非综合征型耳聋患者中GJB2和PDS基因的突变频率和突变热点,调查线粒体DNA 12SrRNAA1555G突变的流行频率,试图揭示这些基因与耳聋发生的紧密联系,探讨耳聋预防的策略和科学有效的治疗途径;并为一遗传性耳聋大家系明确分子病因,进而探讨mtDNA突变同非综合征型耳聋之间的关系。本研究主要包括以下三个部分:
第一章:Waardenburg综合征的临床特征及相关基因突变研究
我们对来自中南地区的19例Waardenburg综合征患者进行了临床诊断和分型,对其中5例WS1进行PAX3基因突变检测,另14例WS2进行MITF、SNAI2和SOX10基因突变检测。结果发现WS患者临床表型变异很大。所有患者均有虹膜异色;89.5%的患者表现为双侧对称的先天性极重度感音神经性耳聋,且以WS2中多见;同时,4例WS2(28.6%)表现为全身皮肤棕褐色雀斑沉着,其它症状如白额发、早白发等仅见于个别病例。共在16例WS中发现10种基因突变位点(PAX3和MITF基因各3种,SOX10基因4种),另3例突变检测阴性。所有WS1均携带PAX3基因突变,35.7%和42.9%的WS2患者分别检测到MITF和SOX10基因突变;其中8种(PAX3:H80D和H186fs;MITF:R217I和T192fs;SOX10:G38fs、R43X、E248fs和G37fs)为未报道新突变。为绘制中国人群WS相关基因突变图谱提供了重要的数据,并为揭示WS的分子致病机制打下了基础。
第二章:非综合征型耳聋常见耳聋相关基因的突变研究
我们采用直接测序、DHPLC和PCR-RFLP的方法对湖南地区汉族139例非综合征型耳聋患者分别进行GJB2、PDS和线粒体DNA12SrRNA A1555G突变的筛查,结果发现43.9%(61例)的患者至少携带其中一种基因突变;GJB2、PDS和线粒体DNA 12SrRNAA1555G突变的检出率分别为23%、18.7%和3.6%;共发现6种GJB2和13种PDS基因致病性突变,其中1种GJB2基因新突变(F115C)和3种PDS基因新突变(S8X、A227P和Cys565fs):235delC和IVS7-2A>G分别是GJB2和PDS基因最常见的突变类型,分别占这两个基因突变的89.1%和46.5%;通过此次筛查,为其中35.3%的患者明确了分子病因,为该地区进一步开展遗传咨询、基因诊断和产前诊断提供了重要的依据,并为临床用药提供指导。
第三章:一母系遗传非综合征型耳聋大家系的临床特征和分子病因学研究
我们对一母系遗传性耳聋大家系的临床特征进行归纳总结,并采用直接测序法对先证者进行线粒体全基因组序列分析,结果发现此家系内58.3%(21/36)的母系成员均表现为双侧对称、以高频下降明显的感音神经性耳聋,但发病年龄和耳聋的严重程度变异很大;氨基糖甙类抗生素与该家系部分成员的耳聋关系密切。序列分析共发现23种变异,其中T1541C为新突变。18例母系成员均同时携带12SrRNAA1555G和T1541C同质性突变。5例父系亲属及配偶听力正常,1555和1541位点突变检测阴性。
本研究最后得到以下结论:
(1)Waardenburg综合征临床表型变异很大,以WS2较多见;虹膜异色和感音神经性耳聋为WS最常见的症状;棕褐色雀斑沉着可能是中国人群WS患者皮肤色素改变的一种特殊的形式;PAX3基因突变是导致WS1患者致病的主要原因,而WS2中MITF和SOX10基因突变较欧美人群有更高的检出率,且SOX10基因突变更常见。研究发现10种基因突变位点,其中8种为新突变,表现出中国人群WS患者独特的基因突变谱。3例突变检测阴性提示可能存在其它未知的WS2致病基因。
(2)湖南地区汉族人群三项常见耳聋基因的筛查提示有43.9%的患者携带有常见耳聋基因突变,反映湖南地区遗传性聋高发的现象。GJB2基因突变是导致该地区汉族NSHL最常见的原因,其次为SLC26A4基因。235delC、IVS7-2A>G和A1555G突变分别是GJB2、PDS和线粒体DNA基因的热点突变,占所有突变的71.2%,可利用热点突变进一步开展快速筛查工作。通过本研究为其中35.3%的患者明确了病因。研究发现的1种GJB2和3种PDS基因新突变,进一步丰富了中国人群的耳聋基因突变谱。
(3)母系遗传性非综合征型耳聋主要表现为双侧对称、以高频下降明显的感音神经性耳聋,但发病年龄和耳聋的严重程度变异很大。mtDNA 12SrRNA A1555G突变是该家系耳聋的主要分子基础;环境因素和核基因可能参与A1555G突变表型表达的调节;T1541C为未报道新突变,可能对该家系A1555G突变所致耳聋的外显率有影响。
With the development of molecular biology and genomics,it's a research hotspot to explore the causes of hereditary deafness at the genetic level.Since the majority of Chinese hereditary deaf people had been confirmed to be caused by GJB2,SLC26A4 and mtDNA gene mutations,genetic testing of these three genes can not only make clear about cause of deafness but also provide theoretical evidences for genetic counseling.Furthermore,it makes prenatal diagnosis possible for deaf families.Now,many provinces has investigated the molecular epidemiology of the common deafness genes including GJB2,SLC26A4 and mtDNA A1555G mutations.But no similar research has been carried out in Hunan province.
Meanwhile,there has been remarkable progress being made on syndromic hearing loss.Waardenburg syndrome is one of the most common dieases of SHL.So far,more than 100 gene mutations have been reported in Western WS patients,which disclosed its possible molecular mechanisms.But few WS patients had been reported in China,and very few reports had been observed on the molecular genetic background of WS in Chinese population.
The purpose of the present study,through systematic study on clinical features and molecular genetics of patients with SHU、NSHL or maternally inherited nonsyndromic deafness,is to explore the molecular genetic background and relationship between genotype and phenotype of WS in Chinese population;To investigate the prevalence and hot spots of GJB2 and PDS genes and to estimate the incidence of the mitochondrial 12S ribosomal RNA A1555G mutation in subjects with NSHL in Han people of Hunan province,and try to disclose the mechanism of deafness associated with these genes and provide some theories or suggestions for preventing and curing this kind of hearing loss;Also to study the molecular etiology of a large family with maternally inherited nonsyndromic deafness and then to explore the relationship between mtDNA gene mutations and NSHL.We carried out our research as the following three parts:
Part one:The clinical features and gene mutations in patients with Waardenburg syndrome.
We analyzed the clinical features of 19 WS patients came from central south in China,in which 5 were diagonosed as WS type 1,while other 14 were WS type 2.All the WS1 patients were screened mutations for PAX3 gene and WS2 for MITF,SNAI2 and SOX10 gene mutations.We observed obvious phenotypic variability in Chinese WS patients.All the patients showed heterochromia iridis,and 89.5%patients displayed bilateral, congenital sensorineural hearing loss which was more common in WS2. We also observed 4 WS2 patients(28.6%) manifested much brown freckles on the skin,while other symptoms such as white forelock and premature greying could only be seen on a few patients.At molecular level,totally 10 mutations(3 mutations in PAX3 and MITF genes respectively,and 4 in SOX10) were identified and 8(H80D and H186fs in PAX3,R217I and T192fs in MITF,G38fs,R43X,E248fs and G37fs in SOX10) of them were novel.All the WS1 patients carried PAX3 gene mutations,while 35.7% and 42.9%of WS2 cases were detected MITF and SOX 10 gene mutations respectively.These results have provided important data to depicted the mutational spectrum in Chinese WS and the starting point to discover the underlying molecular mechanism of the disease.
Part two:Mutation analysis of common deafness genes in non syndromic hearing loss patients.
We carried out mutation screening of GJB2,PDS genes and mtDNA A1555G for 139 patients with NSHL in Han people of Hunan province by direct seqence,DHPLC and PCR-RFLP respectively.The study showed 43.9%patients carried at least one of the common genes mutations.The mutation detection rate of GJB2,PDS genes and mtDNA A1555G were 23%,18.7%and 3.6%respectively.Totatlly 6 GJB2 and 13 PDS gene mutations were identified,among them 1 GJB2(F115C) and 3 PDS(S8X, A227P,Cys565fs) gene mutations were novel.89.1%of GJB2 gene mutations was 235delC and 46.5%of PDS was IVS7-2A＞G,which implied 235delC and IVS7 -2A＞G were the most common mutations in the two genes.We made clear about the molecular etiology of 35.3%patients through this study,which supplied important data for further step to genetic counseling,gene diagnosis and prenatal diagnosis and also supplied instructions for clinical medication.
Part three:Clinical characterization and molecular genetic study of a large family with maternally inherited non-syndromic deafness.
We evaluated the clinical features of a large family with maternally inherited nonsyndromic deafness,and carried sequence analysis of the mitochondrial genome from the proband.The results showed 21 of 36 maternal members(58.3%) exhibited symmetric bilateral sensorineural hearing loss especially in high frequency,with a wide range of severity and ages at onset.Deafness of some maternal members was closely related to aminoglycoside antibiotic.Totally 23 variations were found by molecular analysis in the proband.18 maternal relatives harbored the homoplasmic mutation A1555G in thel2SrRNA gene,also a novel mutation T1541C.5 spouses and paternal relatives had nomal hearing and were negative of A1555G and T1541C mutations.
Conclusions:
(1) There are obvious variations in clinical features of WS,WS2 is more common than WS1;Heterochromia iridis and sensorineural hearing loss are the most common symptoms,while brown freckles may be a special type of pigmentary disturbance of the skin.Genetically,PAX3 mutations are mainly associated with WS1.The mutation detection rate of MITF and SOX10 genes in Chinese WS2 patients are higher than in European population,and SOX10 gene mutations are more common than MITF.Totally 10 different gene mutations were identified and 8 of them are novel,which implies the unique mutational spectrum in Chinese WS. No mutations were found in 3 WS2 patients,which means some other unknown genes related to WS2.
(2) There are about 43.9%patients with NSHL carried the common deafness gene mutations,which indicates high incidence of hereditary deafness in Han people of Hunan province.GJB2 gene mutations are the most common cause of NSHL,then PDS gene mutations.235delC, IVS7-2A＞G and A1555G are the hot spots in GJB2,PDS and mtDNA genes mutations respectively,which account for 71.2%of all three gene mutations.We can use the hot spot mutations to develop fast screening for the common deafness genes.The etiology of 35.3%patients in this study have been determined.1 GJB2 and 3 PDS novel gene mutations multiplied Chinese mutation map.
(3) The chacterization of maternally inherited nonsyndromic deafness is mainly symmetric bilateral sensorineural hearing loss especially in high frequency,with a wide range of severity and ages at onset.Mitochondrial mutation A1555G is mainly responsible for the disorder in this family. Environmental determinants and nuclear background may play a role in the clinical expression of deafness,T1541C is a novel mutation in Chinese population,and it may influence the penetrance of deafness due to A1555G mutation.
引文
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