与Connexin26基因突变相关的综合征耳聋和非综合征耳聋

Connexin26基因其编码的产物为一种缝隙连接蛋白，组成的质膜通道蛋白，在细胞间的连接和递质的传递中起着重要的作用。近年来的研究发现此基因的突变与遗传性综合征耳聋和非综合征耳聋密切相关，对这一基因的研究可使我们对耳聋的致病机理有更加深入的了解。     

内耳Connexin缝隙连接的功能与耳聋机理

缝隙连接对于维持正常听觉功能有着重要的作用，编码组成缝隙连接蛋白的Connexin基因突变可引起严重的听力损失．占整个新生儿耳聋病例的70—80％。此类基因病理变化仅发生于耳蜗内，虽听觉毛细胞上并无缝隙连接或Connexin基因表达，但其支持细胞借助于缝隙连接的耦合作用在内耳联结成一个特殊的网络。本文总结了近年来内耳缝隙连接生物物理学特性方面的研究进展，阐述了耳蜗缝隙连接对于听觉功能的重要性；同时也展望了阐明其功能对治疗因Connexin基因突变所致的遗传性耳聋的前景。     

MYO7A基因突变与遗传性耳聋

耳聋是临床上最常见的遗传性疾病之一。在所有耳聋患者中,遗传性聋约占50%,在所有先天性聋儿中,60%以上由遗传因素引起。与遗传性耳聋相关的基因大约有200多个,     

非综合征性耳聋患者连接蛋白26基因突变的研究

目的 探讨中国人非综合征性耳聋患者连接蛋白２６（ｃｏｎｎｅｘｉｎ２６,Ｃｘ２６）基因突变频率和特性。方法 收集中国散发先天性聋哑儿童１６例,常染色体隐性遗传性聋３９例（３９个家系）,１０岁前的听力下降的常染色体显性遗传性聋３０例（３０个家系）和健康对照组１００例。聚合酶链反应－单链构象多态（ｓｉｎｇｌｅ ｓｔｒａｎｄ ｃｏｎｆｏｒｍａｔｉｏｎａｌ ｐｏｌｙｍｏｒｐｈｉｓｍ ａｎａｌｙｓｉｓ ｏｆ     

PRPS1基因突变与遗传性耳聋

磷酸核糖焦磷酸合成酶（phosphoribosylpy-rophosphate synthetase,简称PRS,EC2.7.6.1）,又称核糖磷酸焦磷酸激酶（Ribose-phosphate pyrophos-phokinase）,是体内唯一的催化磷酸核糖焦磷酸（PRPP）合成的酶,而PRPP是体内嘌呤、     

GJB2基因突变及语前遗传性非综合征性耳聋

编码缝隙连接蛋白Connexin-26（Cx-26）的基因称为GJB2基因,该基因的突变被认为是语前遗传性非综合征性耳聋的分子遗传基础.编码GJB2基因突变的证实给遗传咨询提供了帮助.本文综合目前GJB2基因的突变及其在遗传性耳聋发病机制的作用和检测方法、治疗等方面做一简要论述.     

LMX1A突变致遗传性耳聋的研究进展

LMX1A是LIM同源盒基因家族成员（LIM-homeobox）之一,编码LIM同源盒转录因子,是决定许多细胞分化及器官形成的关键转录因子,在内耳的结构形成中发挥重要的作用。该基因包含两个LIM结构域和一个同源结构域,LIM结构域介导蛋白质与蛋白质的相互作用;同源结构域与DNA结合有关。该基因具有基因多效性,不同突变可分别导致常染色体显性/隐性遗传性耳聋,临床表现多变,包括重度-极重度听觉丧失、渐进性听力损失等不同的听力表型,部分患者可伴有前庭功能障碍。目前在全世界范围内报道的与遗传性耳聋相关的LMX1A的变异型共有10种。其中,单倍体剂量不足导致的部分功能丧失是LMX1A变异致聋的主要原因,LMX1A的表达下调会影响内耳发育及毛细胞形态的长期维持,从而导致听觉障碍。对该基因的功能学研究有助于人们了解听觉及神经系统的发育及相关遗传性耳聋的分子机制。     

大连地区108例非综合征性耳聋者及亲属耳聋基因测序结果分析

目的了解大连地区非综合征性耳聋者及直系亲属耳聋基因突变情况。方法收集大连地区非综合征型耳聋患者及部分直系亲属共108例(患者98例,亲属10人),行纯音测听、声导抗测听及脑干诱发电位等听功能检查,采集末梢血用Ion torrent半导体测序方法,检测GJB2、GJB3、GJB6和SLC26A4基因的全外显子和线粒体12S rRNA基因的2个突变位点。结果病理性基因突变在108例受检者中检出率为41.7%(45/108),98例患者中检出率为38.8%(38/98),涉及3个基因23个突变位点,发现1例非常罕见的SLC26A4 IVS15-2A>T剪接位点杂合突变。38例患者中34例(89.5%,34/38)为单基因突变,其中13例为复合杂合突变、6例为纯合突变;另外4例(10.5%,4/38)有两个基因同时发生突变。38例患者的42例次基因突变中,27例次(64.3%,27/42)为GJB2基因突变,12例次(28.6%,12/42)为SLC26A4基因突变,3例次(7.1%,3/42)为GJB3基因突变,没有检测到GJB6、12S rRNA基因突变;听力筛查不通过、经ABR测试为中重度感音神经性耳聋患儿33例,15例(45.5%,15/33)检测到病理性基因突变;成人散发性双耳感音神经性耳聋患者62例,病理性基因突变检出20例(32.3%,20/62)。结论大连地区98例非综合征性耳聋者,超过1/3检测到病理性耳聋基因突变,并以GJB2基因突变最常见。听力筛查通过的高危儿童及原因不明的双侧感音神经性耳聋者,实施热点致聋基因测序可以提高耳聋的病因诊断率。     

江苏南通地区非综合征性耳聋GJB2基因突变分析

目的 研究南通地区非综合征性耳聋GJB2基因突变情况。方法 收集南通地区海安县和如皋县聋哑学校学生100名和健康对照组50名，利用PCR扩增及限制性内切酶酶切分析初筛GJB2 235delC突变者，然后再行DNA直接测序。结果 耳聋组中共发现三种突变：235delC、176—191del16、299—300delAT。235delC是主要突变方式．约30％的患者携带此突变；299—300delAT和176-191del16突变检出率分别为9％和8％。对照组未发现这些突变。结论 南通地区非综合征性耳聋GJB2基因突变率较高，因此在南通地区进行广泛的生育前耳聋基因筛查工作有重要意义。     

闽南地区聋儿常见耳聋基因突变分析

目的研究闽南地区先天性听力障碍儿童常见耳聋基因GJB2和SLC26A4的突变频率、突变类型及这些突变与耳聋的相关性,明确该地区的热点突变情况。方法对厦门市妇幼保健院耳鼻喉科89例非综合征性耳聋患儿进行听力学评估、专科检查及问卷调查,采集其外周血并提取DNA用二代测序法进行遗传性耳聋基因GJB2和SLC26A4全部外显子区域的测序,总结检测到的各种基因突变类型。结果 GJB2基因和SLC26A4基因阳性检出率为46.07%,其中阳性确诊病例24.72%,疑似病例21.35%;GJB2基因阳性检出率高达33.71%,SLC26A4基因阳性检出率为11.24%。结论本次实验表明对听力障碍儿童进行常见的耳聋基因GJB2和SLC26A4的筛查有较高的检出率,并且部分患儿能从分子水平进行诊断。进行常见耳聋基因的检查可以今早的发现遗传性耳聋患者,对防聋、控聋起到一定的指导意义。     

Differences in hearing levels between siblings with hearing loss caused by GJB2 mutations

ObjectiveHearing loss caused by GJB2 mutations is inherited in an autosomal recessive manner (DFNB1); thus siblings of an affected child have a 25% chance of also being affected. Hearing loss among subsequent siblings carrying the same GJB2 mutation is a concern for parents and a frequent topic of enquiry during genetic counseling. Evidence exists for genotype-phenotype correlations of GJB2 mutations; however, no analysis of differences in hearing among siblings, in whom the common genetic background may decrease variation, has been reported. The purpose of the present study was to investigate hearing differences between siblings with identical GJB2 mutations.MethodsWe examined the hearing levels of 12 pairs of siblings; each pair had the same pathogenic GJB2 mutations. Differences in hearing acuity between sibling pairs detected by auditory evaluation.ResultsNo significant correlation was detected between the average hearing levels of first and second affected siblings. Average differences in acoustic threshold >30 dB were observed between four pairs of siblings, whereas the remaining eight pairs had average threshold values within 20 dB of one another.ConclusionOur results indicate that auditory acuity would be expected to approximate that found in the first child in approximately 70% of subsequent children with GJB2-mediated hearing loss, whereas 30% of subsequent siblings would have average differences of >30 dB.     

KCNQ4基因突变对常染色体显性遗传性聋家系的影响

目的 应用选基因法了解KCNQ4基因对中国耳聋家系的影响，检测其突变形式。方法 在一个6代相传的常染色体显性遗传性家系中，应用聚合酶链反应－单链构像多态性（polymerase chain reaction-single strand conformation polymorphism,PCR-SSCP)及克隆测序方法对KCNQ4基因的全部编码序列的PCR产物进行突变位点及多态序列检测。结果 在该家系中，对36位家系成员进行了KCNQ4基因的编码序列的检测，发现KCNQ4基因外显子2的分子多态现象，经测序分析证明这种多态是由于内含子中47个碱基复制数的差异所造成的。结论 本实验证明KCNQ4基因外显子2的编码区附近存在一个新的分子多态标记，这种分子多态表现出不同的基因型。通过对这些基因型与耳聋表型的相关分析发现，随着内含子复制数的增加，耳聋表现度明显增加。提示KCNQ4基因外显子2与外显子3之间内含子复制数的变化可能是这个家系出现耳聋的一种特征性分子标记。     

Familial nonsyndromic hearing loss with incomplete partition type II caused by novel DSPP gene mutations

Background: Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II (IP-II) is a very rare condition.

Aims/Objectives: To determine the audiological feature, inheritance patterns and genetic etiology of familial NSHL with IP-II in a Chinese family with eight family members.

Material and methods: Clinical data were collected from all eight family members, selected deafness genes were sequenced in proband and whole genome sequencing of seven family members was performed.

Results: The proband were a pair of male nonidentical twins (III:1, III:2). Three patients in this family, including the twins and their father (II:1), were diagnosed with bilateral NSHL with IP-II, and no mutation was found in the genes of SLC26A4, GJB2, GJB3, mitochondrial 12S rRNA, and MITF. Whole genome sequencing data indicated de novo mutations of the gene DSPP, c.3085A?>?G and c.3087C?>?T, which resulted in p.N1029D and co-segregated with deafness phenotype, were the underlying genetic etiology.

Conclusion and significance: Familial NSHL with IP-II is extremely rare. In this family, de novo DSPP gene mutations, were considered to be the most probable genetic etiology. And this is the first report to reveal DSPP gene mutations leading to familial NSHL with IP-II.     

缝隙连接蛋白31基因与遗传性耳聋

遗传性耳聋作为-种单基因疾病,具有明显的遗传异质性,迄今共有187个耳聋位点（54个为常染色体显性位点,67个为常染色体隐性位点,8个X-连锁位点,2个修饰基因位点,1个Y-连锁位点,1个听神经病基因位点,13个线粒体DNA突变位点．8个与耳硬化症有关的基因位点．33个与综合征性耳聋有关的位点）见诸报道,已克隆的听觉基因共73个,其中45个与非综合征性耳聋有关。研究表明,耳聋与多种缝隙连接蛋白（Connexin,CX）突变有关．缝隙连接对于维持正常听觉功能有着重要的作用。人耳可听到的声音频率在20～20000Hz之间．并可感受到相差100万倍以上的声强变化。听觉器官的灵敏度与频率选择性分别为听力阈值与语言识别能力的基础。     

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.     

Clinical picture of hearing defects caused by Cx26 gene mutations

The study of prevalence of Cx26 gene mutations in children suffering from congenital and prespeech non-syndromal hypoacusis was conducted in Russian population since 2001. The screening of this group of children showed that 35delG mutation occurred in 53%. This index depends on the region and clinical characteristics of the groups studied. Thus, in the family burden it increased to 65% and more. The article presents clinical characteristics of hearing problems caused by 35delG mutation in Cx26 gene. Clinical evidence was obtained on 197 patients with the affected genotype (146 homozygotes and 51 heterozygotes by deletion). Most of deletion homozygotes were diagnosed early (under 1 year) and had bilateral neurosensory hypoacusis with frequent severe hearing loss (75.7%). No family burden was seen in 47% patients with abnormal genotype. In the group studied only 24% cases had no familial burden. 20% children were born by mother with abnormal pregnancy and delivery, 2.5% had the history of severe infections except meningitis, 11.7% - of first year diseases. Cx26 gene mutations were diagnosed in half cases of hypoacusis in children whose parents attribute hearing loss to administration of antibiotics.     

Cx26 gene mutations in idiopathic progressive hearing loss

OBJECTIVE: The present study evaluated the frequency and type of mutations throughout the entire GJB2 region in a population of 39 patients affected with sporadic progressive "idiopathic" hearing loss. MATERIAL: A large series of patients suffering from progressive hearing loss underwent a systematic screening program to identify the etiology of the hearing loss. Of these patients, 39 presented with sporadic idiopathic progressive hearing loss and were included in this study. METHOD: We performed molecular analysis of GJB2 in each patient sequencing the genomic deoxyribonucleic acid (DNA) in both directions for detection of GJB2 mutations. Furthermore, in all patients bearing a Cx26 mutation, a search was also conducted for mutations or deletions of GJB6 (Cx30 gene) and for the A1555G mutation of the mitochondrial DNA. A control group was also considered to evaluate the frequency of Cx26 mutations in the normal population. RESULTS: A Cx26 gene mutation was detected in nine cases. One subject was found to bear a homozygous genotype for the 35delG mutation, another subject was compound heterozygous for 35delG and E47X, and the remaining patients showed heterozygous genotypes (35delG, L90P, R127H, M34T, V153I, V37I). No mutation or delection of the Cx30 gene was observed in these nine patients, and none of them presented with the A1555G mutation in the mitochondrial DNA. In the control group (40 individuals), a Cx26 mutation was detected in two cases (5%). CONCLUSIONS: About 23% of our patients (nine subjects) presented with mutations in GJB2, and 18% (seven subjects) were heterozygous. However, most of the described mutations are recessive, so a monogenic model of inheritance cannot explain the deafness phenotype. On the basis of these findings, we can speculate that the heterozygote Cx26 genotype could be a cause of progressive hearing loss, probably in association with mutations in other alleles. Thus, we recommend carefully following all hearing-impaired subjects with GJB2 mutations, even if they present with only mild hearing loss, because the hearing deficit could worsen. Furthermore, molecular analysis of the Cx26 gene should also be performed in adult patients affected with idiopathic progressive hearing loss.     

辽宁地区非综合征型耳聋患者常见耳聋基因突变分析

目的：分析辽宁地区重度和极重度非综合征型耳聋患者常见耳聋基因热点突变的特点及规律。方法：收集中国医科大学附属第一医院就诊的非综合征型耳聋患者128例,采集外周血并从中提取DNA,应用耳聋基因芯片检测中国人群中常见的4个基因GJB2、GJB3、SLC26A4、线粒体12SrRNA的热点突变位点,同时结合耳聋问卷调查、听力学检测及颞骨CT检查。结果：128例患者中52例（40．6％）存在不同的被检测基因位点突变：①22例存在GJB2基因突变,其中c．235delC位点纯合突变10例,单杂合突变5例c.176_191 del 16位点单杂合突变1例;c.35 del G位点单杂合突变1例;c．235 del C／c．299_300 del AT复合杂合突变1例,C．235delC／c．176_--191del16复合杂合突变1例,035delG／c.176_191 del 16复合杂合突变1例;c.299_300 del AT纯合／c．919-2A〉G杂合1例儿235 del C纯合／c．919-2 A〉G杂合1例。②30例存在SLC26A4基因突变,其中c．919-2 A〉G位点纯合突变6例、单杂合突变17例,c．2168 A〉G位点纯合突变1例、单杂合突变2例,c．2168 A〉C／c．919-2 A〉G复合杂合突变2例,c．919-2 A〉G／GJ B2 c．235 del C复合突变2例。③无GJB3和线粒体12S rRNA基因突变,考虑与样本量少有关。在基因水平,明确诊断遗传性聋者24例（18．8％）,遗传性耳聋基因突变携带者28例（21．9％）。结论：辽宁地区耳聋患者存在较高的遗传性耳聋发生率,耳聋基因芯片诊断技术可应用于临床中进行快速筛查、诊断并指导聋儿康复。     

对急性低频感音神经性听力损失患者前庭功能的研究

目的:对急性低频感音神经性听力损失(ALHL)患者进行前庭功能检查,了解该类患者的前庭功能是否异常。方法:对52例ALHL患者在治疗前和治疗后分别进行前庭功能检查,包括眼震电图检查和静态姿势描记图检查,并与对照组进行比较。结果:52例ALHL患者重心晃动的路径总长明显延长,晃动速度明显增快,与对照组治疗前闭眼状态下相比较,差异有统计学意义(P<0.05);治疗前9例(17.3%)眼震电图检查异常,治疗后2例(3.8%)仍异常;治疗后静态姿势描记图检查与对照组比较,差异无统计学意义(P>0.05)。结论:ALHL患者虽无眩晕主诉,但部分患者前庭功能已经受损,在临床工作中应对该类患者行前庭功能检查,以进一步了解其整个内耳功能状态,并应进行长期随访。