【作者】 莫建洪；

【导师】 罗会元； 黄尚志；

【作者基本信息】 中国协和医科大学 ， 医学遗传学， 1999， 博士

【摘要】 无综合征型常染色体显性感音神经性耳聋家系的基因定位——一个新的基因座 本文通过表型鉴定、基因分型和连锁分析，将一个六代相传常染色体显性遗传性耳聋大家系的致病基因定位到9号染色体。这是由我们中国人定位的第一个非综合征型常染色体显性遗传耳聋病基因座（DFNA）。按国际上人类基因命名规则，我们将此新的耳聋基因命名为DFNA23。 家系调查显示，该家族听力损害以典型的常染色体显性方式遗传，已相传六代。病史资料和体检表明耳聋病为非综合征型，即，不伴随任何非听觉症状。从病史和听力图推测，多数受累家族成员的发病过程基本类似，即，大多数患者在生命的第一个十年或第二个十年的初期出现轻度的高频听力缺陷，以后迅速依次向中、低频扩展。最终，30岁以上的患者均发展成为深度聋或全聋。本家系纯音气骨导测试证实为感音神经性耳聋，28例43耳遗传聋经ARI证实为耳蜗性感音性听力损失。 首先，我们应用文献报道的常染色体显性遗传耳聋相关基因座的多态性标记进行等位基因共享分析，结果表明该家系的致病基因与已报道基因座不相关。在此基础上，我们采用PE公司的ABI PRISMTM^TM连锁定位试剂盒（第2版）进行了全基因组扫描，并用Linkage Package 5.2中的Mlink程序对所得到的基因型数据进行了两点连锁分析。我们发现，将基因型数据编制为一个单一大家系文件时，不能证实所有285个实际可用的多态性标记与致病基因连锁；不过，将该家系A、B两支的基因型数据分别编制家系文件，然后合并进行连锁分析，多态性标记N12，在theta=0时，Zmax=3.77，表明该家系中的耳聋基因与此标记存在连锁关系，在随后的精细定位中，Nf1，在theta=0.01时，Zmax=3.22；证实该家系耳聋基因与N12和Nf1所在的9号染色体区域连锁。另外，我们还发现，D4S403在theta=0时，Zmax=2.22，提示连锁关系。不过，由于其与相邻的多态性标记D4S306间距过大（20cM），因此，需要在此间距中选择其它一些多态性标记进行基因分型，以便证实和排除与致病基因的连锁关系。 检索OMIM和GDB，未发现任何已知非综合征征型常染色体显性遗传耳聋病基因座（DFNA）定位于N12所在的9号染色体区域，因此，这是一更多还原

【Abstract】 A disease-causing gene responsible for hereditary hearing impairment in a six-generation family was localized to chromosome 9. It is first time that we Chinese defined a nonsyndromic autosomal dominant deafness gene locus （DFNA） by ourselves. Based on the regulation of Human Gene Nomenclature, the novel DFNA is designated as DFNA 23.Family investigation demonstrated that hearing impairment in the family is inherited in a classic autosomal dominant mode and passed along is six generations. Diagnosis of nonsyndromic autosomal dominant , progressive neurosensory hearing loss was based on the medical history , physical examination and audiological evaluation of the family numbers. It is inferred that the hearing loss begins in the first decade of life or early second decade of life, according to the medical history and audiometry, and it first affected high frequence mildly, then progressed in turn to mid and low frequencies quickly. finally, all affected member in the family became severe to profound deafness at age of 30 or above. The pure tune audiometry of both air and bone conduct showed neurosensory deafness, and cochlear sensory hearing loss is confirmed in hereditary deafness of 43 ears from 28 cases.Allele sharing analysis was carried out with previously reported genetic markers linked to known DFNA loci. As result of it, no evidence of linkage of the gene responsible for merged. On the basis of the allele sharing study, a genome-wide scaning was performend with ABI PRISM^TM Linkage Mapping Set Version 2.0 for the DFNA in the family. Two-point linkage analysis has been done by use of Mlink program of Linkage package 5.2. We found that the hereditary deafness in the family is allele heterogenous, because no evidence of linkage of disease-causing gene for the DFNA in the family was confirmed with 285 polymorphism markers available, when a single big pedigree file was used. However, when two pedigree files were combined for linkage analysis, which was made up respectively from branch A and B, we obtained significant Lod score above 3, for marker N12, when theta=0, Zmax=3.77, Nf1, theta=0.05, Zmax=3.22; and D4S403, when theta=0, Zmax=2.22, which showed suggestive evidence of linkage. The results demostrated comfirmative evidence of linkage of a gene responsible for the DFNA in the family with a location on chromosome harbourng Marker N11. As for D4S403, whereas there is a big gap of 20 cM or更多还原