摘要
耳聋是导致言语交流障碍的常见疾病，在世界范围发病率是每1,000名新生儿中就有一名先天性耳聋的患者，其中有50％是由遗传因素引起的。从20世纪90年代至今，引发遗传性耳聋的基因的定位与克隆取得了突破性的进展。研究表明，耳聋有着高度的遗传异质性，涉及众多的基因。尽管耳聋基因的发现已经取得了显著进步，但还有未知的耳聋基因等待我们去发现，对已知耳聋基因的功能仍需深入研究。对遗传性耳聋致病基因以及它们的分子遗传机制的研究，无论是对阐明人类听觉功能的分子机制，还是对耳聋的临床防治，都具有重要的意义。
遗传性耳聋分为综合征型和非综合征型，其中非综合征型耳聋又分为常染色体显性遗传(DFNA，约70％)、常染色体隐性遗传(DFNB，约15～20％)、x染色体连锁遗传(DFN)和线粒体突变(小于1％)。
在本研究中，我们利用了经典的连锁分析的方法，对1个常染色体显性遗传的非综合征型耳聋(DFNA)大家系NMG-L024，进行了相关耳聋基因的定位研究和突变筛查。该家系6代相传，患病个体表现为常染色体显性感音性进行性耳聋，患病初期为高频下降，逐渐引起全频下降并最终耳聋。
实验采用常染色体上的微卫星标记对家系的全基因组扫描和连锁分析，结果表明该家系的致病基因被定位于7号染色体的短臂端7p15.1—7p15.3区域。选取该区域的9个微卫星标记进行精细定位的研究，利用其中的6个微卫星标记对家系作了单倍型分析，发现患者个体Ⅳ：2在D7S629，Ⅳ：16、Ⅳ：17在D7S526的位置上发生了交换，在D7S2457的位置得到了最大的LOD值5.39(θ=0)。从而将该致病基因定位于微卫星标记D7S629和D7S526之间的12cM区域。
在此区域当中，DFNA5被作为首选的候选基因进行突变位点的筛查。通过测序的方法，我们在DFNA5基因中发现了与NMG-L024家系表型共分离的1个新的突变位点—ⅣS8+4 A→G。我们对整个家系和选取的100个纯音测听正常人对照进行了该位点的酶切检测，均证明了只有家系中的病人发生了该位点的突变。同时，在DFNA5基因的所有外显子以及外显子前后100bp的区域内没有发现别的突变位点。
家系病人的RNA反转录试验结果显示，在转录水平上检测到了外显子8的缺失。该结果进一步证明了家系定位的正确性。
DFNA5基因的功能研究至今没有取得确定的结论，我们希望进一步的工作能够揭开该谜团。
Hearing loss is a common sensory disorder in the human population, approximately 1 in 1000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Congenital deafness in at least 50% of subjects in developed countries is attributed to genetic defects. From 1990 till now, location and cloning of genes related to the hereditary hearing loss have developped so quickly. Hereditary hearing loss is a most common genetic disease in Otorhinolaryngology, also a paradigm of genetic heterogeneity. Although significant advances have been made, there is no doubt that more genes are to be discovered, and the function of the genes should be studied. Study on hereditary hearing loss genes and the molecular mechanism processes involved in the auditory system is important for both clarifying the molecular mechanism of heating and clinical prevention and cure of deafness.
Hereditary heating loss is classified as nonsyndromic and syndromic types. Nonsyndromic hearing impairment can be subdivided by the mode of inheritance: 70% of causes are autosomal recessive (DFNB), 15～20% are autosomal dominant (DFNA), and less then 1% are X-linked (DFN) and mitochondrial inheritance. Remarkable progress has been made in the identification of new loci for nonsyndromic hearing impairment (NSHL) and in the cloning of deafness genes.
In this research, we adopted classical linkage analysis method in mapping the locus for a Chinese DFNA family—NMG-L024 and screen the mutation。The Chinese family with six generations affected members are autosomal dominant progressive sensorineural hearing loss starting in the high frequencies then the mid and low frequencies.
Whole genome scan and linkage analysis were performed, in which autosomal microsatellite markers were used. The disease gene causing hearing loss in this family was localized to the short arm of chromosome 7, in the 7p15.1—7p15.3. Fine mapping with nine STR in the region was performed, and six of them were used to do hyplotype. The result indicated that the crossing over happened in the affected numberⅣ∶2 in D7S629, andⅣ∶16,Ⅳ∶17 in D7S526. The disease gene was located within a 12 cM region between markers D7s629 and D7s526, with a maximum two-point lod (logarithm of differences) score of 5.39 (θ=0) at D7s2457.
Within this region, DFNA5 gene located in 7p15 was considered to be a good candidate of disease-causing gene. By sequencing the coding and flanking region of DFNA5, a novel mutationⅣS8+4 A→G was detected, and no other mutation in any other part of DFNA5 has ever been found. Restriction digestion test in this mutation for whole family members and 100 normal control showed that the mutation was detected only in the cases of this family.
Skipping of exon 8 in the DFNA5 gene has been determined through RT-PCR.
However, till now, the function of the DFNA5 gene has not been known. More work should be done. We hope to find the truth.
引文
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