常染色体显性遗传性耳聋家系的遗传学特征分析

目的 听力损失是中国人群中的常见的感觉障碍性疾病。为了解遗传因素在中国听力损失病人中的作用,对两个中国耳聋大家系进行了遗传特征的分析。方法:家系中的先证者在解放军总医院耳鼻咽喉头颈外科就诊,诊断为感音神经性耳聋。通过先证者对家系成员进行调查并绘制系谱图。对调查的家系成员进行病史、体检、纯音测听及听性脑干诱发电位检查。一些家系成员进行了颞骨CT扫描检查以排除听觉系统的其他病变。结果:两个中国耳聋家系,命名为Z002及F013家系,表现为一种代代相传的中度及中重度听力掘失。遗传方式考虑为常染色体显性遗传方式。在Z002家系的听力表型表现为一种高频听力损失,而在F013家系表现为低频听力损失。结论:本文报道了两个特征为非综合征型的常染色体显性遗传的中国耳聋家系。系谱图分析提示两个家系均为常染色体显性遗传方式。这两个家系适合于进一步的连锁分析及定位克隆研究以便寻找到相应的耳聋相关基因。     

线粒体DNA突变与遗传性耳聋

由于线粒体ＤＮＡ研究方法的限制，线粒体ＤＮＡ突变与人类疾病关系的研究远远落后于核遗传病的认识。近年来由于ＰＣＲ及分子杂交等新技术的应用使线粒体疾病的研究取得了较大的进展，本简要综述了线粒体ＤＮＡ突变与多种遗传性耳聋症的最新分子遗传学研究进展。     

Y-连锁遗传性耳聋:中国一大家系的听力学表型特征

目的进行Y-连锁遗传性耳聋(DFNY1)家系的听力学表型特征分析.方法对DFNY1家系中的50名成员进行的听力学检查,包括Madsen 502便携式听力计(丹麦),EAR-3A插入式耳机(美国)进行家系成员的纯音测听检查;Madsen901(丹麦)声导抗检测仪进行鼓室图及镫骨肌反射的检测;便携式听性脑干诱发电位仪(SmartEPIntelligent Hearing Systems,America.)进行听性脑干诱发电位检测.家系的表型特征根据听力损失的程度定义为耳聋和非耳聋.结果接受听力检测的50名家系成员中发现耳聋患者21名,其中20名为家系中的直系男性,1名为女性.发病年龄在7-27岁之间,平均为12.7岁;67%耳聋患者的听力曲线表现为高频下降型曲线,听力曲线的结构具有相似性.结论本文报道了中国DFNY1耳聋大家系的耳聋患者听力学表型特征为双侧、对称性、学语后的感音神经性听力损失,家系中耳聋患者的听力表型具有均一性,这些特征进一步说明DFNY1家系的致聋基因为单一致病基因.     

连接蛋白与遗传性耳聋

耳聋的遗传基础比较复杂，具有很强的遗传异质性。在人类约有15种连接蛋白，现证实有4种连接蛋白与遗传性耳聋有关，本从它们在组织和器官的表达、突变类型、引起耳聋的机制及临床应用等方面的研究进展进行综述。     

非综合征型耳聋家系的遗传学特征分析

目的分析一个常染色体显性遗传性耳聋家系临床及遗传学表型,并筛查常见耳聋致病基因。方法通过调查问卷、体格检查、听力学检测,完成该湖南籍耳聋家系的临床资料采集,绘制家系遗传图谱,分析其听力学及遗传学特征,对最常见的GJB2,SLC26A4和12S r RNA共3个耳聋基因八个位点以及线粒体DNA全组序列进行初步筛查。结果该家系共5代,现存家系成员35人,耳聋患者10人,除两人发病较晚,余均为自幼发病,听力曲线呈盆覆型,造成部分言语功能障碍,进展性加重,起初为中频受累,随着年龄的增长,以后逐渐累积高低频,表现为全频听力损失,发展为重度-极重度耳聋。对候选致病基因突变筛查,未发现致病突变。结论该耳聋家系符合常染色体显性遗传规律,进一步将通过新一代测序全外显子测序技术对其致病基因进行探索。     

遗传性耳聋家系线粒体DNA 961delT/insC(n)突变的致病性分析

目的 探讨线粒体DNA 961delT/insC(n)突变与氨基甙类药物性耳聋的相关性.方法 对一个耳聋家系11个成员采集氨基甙类抗生素用药史、进行听力学检查、表型分析,采集外周静脉血样本,从白细胞中提取DNA,用聚合酶链反应扩增线粒体DNA(mtDNA)全序列,对扩增片段进行DNA测序,对发现的基因突变与耳聋表型进行分离分析.结果 参与研究的所有9例母系成员均检出mtDNA 961delT/insC(n)突变.有明确氨基甙类抗生素用药史的4例中只有2例耳聋患者,其中1例为用药之前出现的先天性聋,另1例为用药后38年出现的轻度耳聋.突变不与耳聋共分离.结论 本研究不支持mtDNA 961de1T/insC(n)突变是该家系耳聋的致病突变,mtDNA 961位点附近可能是一个多变异的区域,mtDNA 961delT/insC(n)可能是一个与氨基甙类药物性耳聋不明确相关的多态.     

一个遗传性耳聋大家系的基因突变检测

目的 :探讨中国人遗传性耳聋基因的突变热点和明确我们最近收集到的一个遗传性耳聋家系是否为已克隆的耳聋基因的突变所致。方法 :该家系 5代共 4 7人 ,其中耳聋患者 1 8人 ,从家系图分析 ,符合常染色体显性遗传 ;所有患者均为语后聋 ,从 1 6 3 0岁起病 ,为双耳对称性、进行性、高频听力下降为主的感觉神经性聋 ,不伴其它器官系统的异常 ;采用PCR 直接测序法在该家系中进行HDIA1、GJB3、GJB2、DFNA5、а tectorin(可导致DFNA8和DFNA1 2两型遗传性耳聋 )、MYO7A、POU4F3等 7个常染色体显性耳聋基因的突变检测。结果 :发现CX2 6基因有 2种核苷酸改变即A3 4 1G和GC2 5 7 2 5 8CG ;POU4F3基因有 1种核苷酸改变即T90C。分析后发现 ,上述核苷酸改变均不是该家系耳聋的致病性突变。其余 5个基因未发现突变。结论 :该常染色体显性耳聋家系由目前已克隆基因突变所致的可能性较小 ,笔者目前正在进行的全基因组扫描和连锁分析极有可能定位一个新的耳聋基因位点     

线粒体突变与遗传性耳聋

背景 线粒体在真核细胞中的作用是产生细胞生理活动所需能量的中心。而在耳蜗的外毛细胞、支持细胞和血管纹中均含有大量的线粒体,近些年来的研究发现线粒体基因的突变可以导致遗传性综合征和非综合征耳聋。通过对线粒体基因突变的研究可以使我们对耳聋的致病机理有更深刻的了解。"引言" 线粒体是一种椭圆形的细胞器,由双层膜包绕组成,具有内外双层膜结构,两层膜之间为膜间腔。内膜高度皱迭形成许多棘伸入基质。内膜内侧面和棘分布有许多小颗粒,是ATP合成酶系复合体所在处,是合成ATP的场所。此外,在线粒体的内膜上还分布有许多运载体…     

34例遗传性耳聋综合征分析

198 6年～ 1998年在对聋哑人普查及门诊就诊的耳聋病人 3373例中发现 34例与遗传性聋相关的综合征 ,现报道如下 :1　临床资料1 1　Ｕｓｈｅｒ综合征 16例 ,见表 1。1 2　Ｗａａｒｄｅｎｂｕｒｇｓ综合征 15例 ,见表 2。1 3　Ｒｅｆｓｕｍ综合征 1例 :男性 ,2 0岁 ,因双耳听力及双眼视力逐渐减退 ,双下肢痛、麻木感伴行走不稳 2个月 ,入院住神经科。入院检查 :Ｔ、Ｐ、Ｒ正常 ,视力 :左眼 0 2 ,右眼 0 3,眼底黄斑水肿、充血、中心反光消失。纯音测听 :1985年测得言语频率平均听阈右耳为 6 3ｄＢＨＬ ,左耳为 71ｄＢＨＬ ,1990年复查右耳 90…     

南通地区遗传性耳聋资源收集及病因学分析

目的 调查江苏南通地区遗传性耳聋病因流行病学情况。方法 调查南通各市县五个聋哑学校202名学生，利用聚合酶链反应一限制性片断长度多态性（PCR—RFLP）方法和Prev—DAF药物性耳聋基因诊断试剂盒筛查患者GJB2 235delC突变和线粒体DNA 12SrRNA A1555G突变。结果 195例非综合征耳聋患儿中31例（15．9％）为GJB2 235delC纯合突变，21例（10.8％）为GJB2 235delC杂合突变，5例（2．6％）存在线粒体DNA 12SrRNA A1555G点突变，在分子水平能够明确诊断者占2913％。结论 南通地区遗传性耳聋发病率较高，尤其是GJB2 235delC突变，突变率（26％）明显高于全国平均水平（18％）。此结果突出了本地区耳聋基因诊断的重要作用，利用耳聋基因检测技术，在人群中（包括重点人群和普通人群）进行生育前耳聋基因筛查，是达到减少聋儿出生的重要途径。     

特大常染色体显性遗传聋家系听力学特征及候选致病基因突变筛查

目的探讨一中国常染色体显性遗传聋大家系的听力学特征,进行已知致聋基因已知突变位点的筛查。方法经知情同意,对家系成员进行全身检查及听力学检测,获得血样标本;整理分析家系资料并绘制系谱图;用基因组DNA抽提试剂盒提取外周血DNA。对2例家系患者DNA进行GJB2和GJB3基因全部编码区突变检测,对其余23个已知常染色体显性遗传性耳聋(DFNA)基因的74个已知突变位点所涉及的50个外显子进行PCR扩增和直接测序分析。结果该家系共7代199人,现存4代176人,耳聋患者54人。系谱分析显示,耳聋表型代代相传,男女患病人数分别为24和30,符合常染色体显性遗传特征。听力学表现为:迟发性、进行性、双侧对称性、感音神经性听力损失,首先是高频区受损,并快速向中、低频扩展。GJB2、GJB3基因全部编码区及其余23个DFNA基因已知突变位点的序列分析均无阳性发现。结论该家系是一个非综合征型常染色体显性遗传聋大家系,耳聋表型为迟发性、进行性、双耳对称性感音神经性听力损失;初步分子遗传学分析提示可能由新基因或已知基因的新突变致病。     

间隙连接蛋白基因与遗传性聋的相关性研究

目的　分析中国人无综合征耳聋的间隙连接蛋白 (Connexin31,Cx31)基因突变及突变频率和特性 ,从分子水平探讨该病的发病机理。方法　收集中国人 4 7例无综合征耳聋家系先证者 ,38例散发的无综合征耳聋患者以及 10 0例健康对照 ,应用聚合酶链反应 (polymerasechainreaction ,PCR)扩增Cx31基因编码区片段 ,通过变性高效液相色谱法 (denaturinghigh performanceliquidchromatography ,DHPLC)筛查突变 ,经DNA测序证实突变。结果　Cx31基因编码区 798C→T杂合突变在耳聋患者和健康对照组发生率分别为 14 1% (12 / 85 )和 1% (1/ 10 0 ) ,两者间差异具有非常显著性意义 (P <0 0 1)。在一个常染色体显性无综合征耳聋家系中的 2例患者发现Cx31基因编码区 5 80G→A杂合突变 ,导致A194T的错义突变 ,家系中听力正常者及健康对照无此突变。在 1例散发无综合征耳聋患者Cx31基因的编码区 ,发现 2 5 0G→A杂合突变。此外 ,本科题组以往已经对本实验中的耳聋家系及散发耳聋患者和对照筛查了Cx2 6基因突变 ,并发现 2个家系存在Cx2 6基因突变。但本实验在这 2个Cx2 6基因突变引起的无综合征耳聋家系未筛查到Cx31基因突变。而Cx31基因突变者也不存在Cx2 6基因突变。结论　Cx31基因与无综合征耳聋相关 ,在本实验中未发现Cx     

角皮病致病基因GJB4在遗传性耳聋中的研究

目的连接蛋白基因和遗传性耳聋及角皮病有明确的相关性.现有4个连接蛋白基因突变可导致角皮病,即:GJB4、GJB2、GJB3和GJB6,其中3个基因既可导致遗传性耳聋,即GJB2、GJB3和GJB6,而GJB4是否与遗传性耳聋相关还有待于进一步证实.为证实GJB4和遗传性耳聋的相关性,在非综合征型遗传性耳聋中进行突变检测.方法本实验采用PCR-直接测序法对60个非综合征型遗传性耳聋家系先证者进行GJB4的突变检测,其中32个显性遗传,28个隐性遗传.结果发现了四种碱基改变:109G＞A、3'UTR 17 A＞G、611A＞C和507C＞G.109G＞A和3'UTR 17A＞G是新发现的碱基改变,但在家系突变检测中证实为多态.611A＞C和507C＞G两种碱基改变是已报道的多态,611A＞C是我们检测到的最常见的多态.结论本研究发现了GJB4的109G＞A和3'UTR 17 A＞G两种新多态,为今后进一步研究打下了基础,但未能最终证实GJB4为遗传性耳聋的致病基因,可是从该基因背景来分析GJB4仍可能是一个很好的耳聋候选基因,有待于扩大家系收集范围进一步检测.     

Functional study of GJB2 in hereditary hearing loss

OBJECTIVES/HYPOTHESIS: The gene of the gap junction protein connexin 26 (Cx26) was found to be the main causative gene of autosomal recessive nonsyndromic hearing loss (DFNB1). Although 35delG has been known as the major mutation in Western countries, 235delC was reported to be a specific form of mutation in Asian populations. The objective of the study was to identify how 235delC and E114G changes found in the Korean population affected the function of using molecular biological techniques. METHODS: Genes containing 235delC and E114G were cloned into the pcDNA3 vector, and HeLa cells were transfected with the recombinant DNA samples by the liposome complex method. The expression and subcellular localization of Cx26 were determined, using antibodies against amino acid sequences in the intracellular loop (IL) and N-terminal (NT) portions of Cx26. To analyze functions of the as a gap junction channel, we examined Lucifer yellow dye transfer between cells with a scrape-loaded technique. Wild-type (WT) with normal hearing was used as a positive control, and mock transfected cells were used as a negative control. RESULTS: Immunocytochemical analysis showed that cells transfected with E114G and WT gave characteristic punctate patterns of reaction in the cell membrane with both antibodies. However, 235delC cells were not stained with anti-IL antibody but stained slightly just around the nucleus only with anti-NT antibody. In a functional study of, transfer of Lucifer yellow into contiguous cells was detected in both WT and E114G, but no transfer activity was observed in 235delC. CONCLUSIONS: The 235delC mutation showed a loss of targeting activity to the cell membrane and severe deterioration of gap junction activity. For the E114G, we did not find any difference from WT transfected cells.     

The age of diagnosis of sensorineural hearing impairment in children

Objective: To identify factors responsible for delays in diagnosis and treatment of pediatric sensorineural hearing impairment (SNHI), and to assess the thoroughness of medical evaluation in these children. Design: Retrospective analysis. Setting: State-supported school for the deaf. Patients and other participants: 291 children with SNHI, the vast majority of whom are profoundly hearing impaired. Data were collected from the school's database, individual student records, and a parental questionnaire. Main outcome measures: (1) The age of diagnosis and treatment of SNHI; (2) factors leading to a delay in diagnosis; (3) current medical evaluations used to determine the etiology of SNHI; and (4) the level of parental satisfaction with the evaluation process. Results: Many children with SNHI experience delays in diagnosis from the time of first suspicion of hearing loss. Children with a risk factor for SNHI are diagnosed no earlier than children without a risk factor. Caucasian children are diagnosed significantly earlier than either Black or Hispanic children, regardless of socioeconomic status. Inconsistent medical evaluation ensues following the diagnosis of SNHI, and parental satisfaction with this process is low. Conclusions: The average age of diagnosis of SNHI remains unacceptably high. There exists a need to enhance physician awareness of childhood deafness and to develop guidelines for the medical evaluation in cases of pediatric SNHI. Lastly, the importance of parental concern regarding a child's hearing or language development must be re-emphasized.     

Age of identification of hearing impairment in Mumbai--a trend analysis

Implementation of Universal Newborn Hearing Screening (UNHS) has led to lowering the age of identification of congenital hearing loss in children. In the absence of UNHS in Mumbai (India), it is pertinent to establish a data base on the age of identification of permanent hearing loss in children to facilitate affirmative action.

Objective

To study the trend in age of identification (AOI) of hearing impairment in children studying in special schools.

Methods

This retrospective study was a survey conducted on a convenient sample. The authentic data about date of birth and age of identification (AOI) of 510 children were collected through parental interview, and scrutiny of documents like birth certificates, first audiological report maintained in special schools/institutes/hospitals.

Results

Time series analysis of the data concluded that from 1989 to 2008, AOI has reduced by 9.59 months. AOI has not reached one year even by 2008 and is much below the target of three months of age as per the recommendation of Joint Committee on Infant Hearing (2007).

Conclusion

In absence of Universal Newborn Hearing Screening (UNHS) in Mumbai (India) the present efforts do not seem to be enough in lowering the age of identification of hearing loss and policy decision is warranted.     

The genetic load for hereditary hearing impairment in Chinese population and its clinical implication

Objective To understand the genetic load in the Chinese population for improvement in diagnosis, prevention and rehabilitation of deafness. Methods DNA samples, immortalized cell lines as well as detailed clinical and audiometric data were collected through a national genetic resources collecting network. Two conventional genetic approaches were used in the studies. Linkage analysis in X chromosome and autosomes with microsatellite markers were performed in large families for gene mapping and positional cloning of novel genes. Candidate gene approach was used for screening the mtDNA 12SrRNA, GJB2 and SLC26A4 mutations in population-based samples. Results A total of 2,572 Chinese hearing loss families or sporadic cases were characterized in the reported studies, including seven X-linked, one Y-linked, 28 large and multiplex autosomal dominant heating loss families, 607 simplex autosomal recessive hereditary hearing loss families, 100 mitochondrial inheritance families, 147 GJB2 induced heating loss cases, 230 cases with enlarged vestibular aqueduct(EVA) syndrome, 169 sporadic cases with auditory neuropathy, and 1,283 sporadic sensorineural hearing loss cases. Through linkage analysis or sequence analysis, two X-linked families were found transmitting two novel mutations in the POU3F4 gene, while another X-linked family was mapped onto a novel locus, nominated as A UNX1 (auditory neuropathy, X-linked locus 1). The only Y-linked family was mapped onto the DFNY1 locus(Y-linked locus 1, DFNY1). Eight of the 28 autosomal dominant families were linked to various autosomal loci. In population genetics studies, 2,567 familial cases and sporadic patients were subjected to mutation screening for three common hearing loss genes: mtDNA 12S rRNA 1555G, GJB2 and SLC26A4. The auditory neuropathy cases in our samples were screened for OTOF gene mutations. Conclusions These data show that the Chinese population has a genetic load on hereditary heating loss. Establishing personalized surveillance and prevention models for hearing loss based on genetic research will provide the opportunity to decrease the prevalence of deafness in the Chinese population.     

Familial incidence of streptomycin hearing loss and hereditary weakness of the cochlea

During the past 15 years, we have observed 16 families in which 2 or more members had their hearing affected by administration of dihydrostresptomycin (SM). Since the familial appearance of such kind of disease could be understood as the result of their special sensitive constitution for the drug, as with penicillin, familial SM hearing loss did not arouse interest in the field of clinical audiology. Considering the clinical features of SM hearing loss, however, it must be relevant to etiological considerations of some types of progressive hearing loss. More recently, we have observed several additional cases of families, in which some members have a hearing impairment after the administration of SM and some others with no SM administration. This paper is a report of a genetical and audiological study of 3 kindreds. Detailed histories, pedigrees and audiological findings are reported. In conclusion, we suppose that there must be a hereditary susceptibility of the cochlea which perhaps is inherited by a dominant trait; this hereditary susceptibility is triggered by some noxious stimuli and manifests a hearing impairment, as a form of the hereditary progressive sensori-neural hearing loss.     

关于学龄听障儿童听觉言语康复训练的思考

基于家庭的经济状况和家长的文化程度及对残疾子女的重视程度等原因,欠发达地区听障儿童的入学往往偏迟。如何对这些有一定残余听力却错过语言发展关键期的学龄听障儿童进行科学、系统、有效的听觉言语康复训练,使他们更快、更好地发展语言,值得广大特教工作者深思。