皮肤病和神经性耳聋致病基因定位与突变研究
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摘要
遗传性皮肤病和非综合征型神经性耳聋(Nonsyndromic hearing impairment,NSHI)是两大类比较重要的常染色体显性遗传病。本课题对这两类遗传疾病进行了分子遗传学研究,涉及家系鉴定,致病基因的定位和基因突变分析。
第一部分内容是有关遗传性皮肤病的。我们研究了播散性浅表光化性汗孔角化症(DSAP)和寻常型鱼鳞病(IV)。目前为止,DSAP的基因克隆目前还未完成,其病理发生机制也仅限于推测。而寻常型鱼鳞病(IV)发病率很高,有报道称其发病率仅次于感冒,是目前遗传性皮肤病中的研究热点。本论文以我们实验室采集并鉴定的一个DSAP大家系和二个IV家系为基础,对这两种遗传性皮肤病进行了分子遗传学研究。
⑴我们鉴定了一个患有DSAP的中国家系,通过全基因组扫描和连锁分析,首先排除了该家系与已知位点或候选基因的连锁,然后在染色体上1p31.3-p31.1区域,发现了一个新的DSAP连锁位点,在D1S2897获得最大两点LOD值5.09。单倍型分析将该位点精细定位于D1S438和D1S464之间8.2cM,或11.9Mb的范围内。这一结果是迄今为止世界上报道的有关DSAP的第三个遗传位点,对该家系在该位点中的基因进行系统的检测,将有可能发现一个新的DSAP致病基因。对这一课题的进一步研究将有助于阐明DSAP的病理发生机制。
⑵我们鉴定了二个患有IV的中国家系。首先排除了这两个家系与FLG基因和其它鱼鳞病亚型相关疾病致病基因的连锁。通过对其中一个大家系的全基因组扫描和连锁分析,在染色体上10q22.3-q24.2区域得到了最大两点LOD值3.19。单倍型分析将该位点精细定位于D10S569和D10S1709之间20.7cM或20.3Mb的范围内。第二个家系也与该位点连锁,最大LOD值达到3.95。两个独立家系都与该位点连锁的结果,强有力地表明了这一位点内存在一个新的IV致病基因,这是已报道的第二个IV遗传位点,我们的研究为找到新的IV致病基因提供了可能。鉴于目前只有一个IV致病基因被发现,找到一个新的IV致病基因将极大地促进IV的发病机理研究。
第二部分内容是有关遗传性皮肤病的。耳聋严重影响患者的生活,而且发病率很高。非综合征型神经性耳聋(NSHI)是人类最常见的听觉损伤,有很高的遗传异质性,其中15～20%为常染色体显性遗传(DFNA)。ACTG1基因突变可以导致DFNA,它编码的蛋白产物γ-肌动蛋白是一种细胞质的非肌肉肌动蛋白,是耳蜗听觉毛细胞主要的细胞骨架蛋白。
在一个患DFNA的中国人家系中,我们发现致病基因与微卫星多态标记D17S928连锁,进一步的单倍型分析将其定位D17S928和D17S784之间。对该区域内ACTG1基因测序,发现了一新的突变,第122位氨基酸由异亮氨酸变为缬氨酸(c.364A>G;p.I122V)。该突变在家系中与疾病共分离,同时对150个正常对照的RFLP分析也没有发现该突变。鉴于以往有关DFNA研究的家系都来自于欧洲和美洲,我们的结果在一定程度上说明ACTG1基因突变也是导致中国人DFNA的一个重要因素。
Inherited skin disease and nonsyndromic hearing impairment are two important autosomal dominant diseases. In the present study, we have employed the molecular genetic technology, including clinical characterization of large families, linkage mapping of the chromosomal location of the disease causing genes, and mutational analysis, to study the two types of diseases.
The first part of the thesis focuses on inherited skin diseases. We studied disseminated superficial actinic porokeratosis (DSAP) and ichthyosis vulgaris (IV). To date, no specific genes for DSAP have bene definitvely identified, however, there are two genes that have been mapped to chromosomes 12 and 15. In this study, I mapped the third genetic locus for DSAP to chromosome 1. IV has a high prevalence rate, which is ranked the second only after influenza. For IV, there is only one gene, FLG, that has been identified. In this study, I mapped the second genetic locus for IV.
⑴A Chinese DSAP family with autosomal dominant inheritance was identified and clinically characterized. Genome-wide linkage analysis was performed and the known loci or candidate genes were excluded. Further analysis identified a new DSAP locus on chromosome 1p31.3-p31.1 with a maximum two-point LOD score of 5.09 with marker D1S2897. The disease gene was defined within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP (DSAP3). Further mutational analysis of the candidate genes in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP.
⑵Two Chinese families with autosomal dominant IV were clinically and genetically characterized. The FLG gene and other ichthyosis associated genes were first excluded as the disease-causing gene in the two families. The larger family was then characterized by genome-wide linkage analysis to identify a new genetic locus for IV. Significant linkage was identified with markers on chromosome 10q22.3-q24.2 with a maximum LOD score of 3.19. Fine mapping defined the new genetic locus within a 20.7 cM region between markers D10S569 and D10S1709. The second family also showed positive linkage to the same region. The combined maximum LOD score in the two families was 3.95. Identification of linkage in two independent families provides strong genetic evidence that a novel gene for IV is located on chromosome 10q22.3-24.2. Future studies of the candidate genes at the 10q IV locus will identify a specific gene, which will provide insights into the pathogenesis of IV.
The second part of the thesis focuses on genetics of hearing loss. Hearing loss severely affects the quality of life, and has a high prevalence rate. Non-syndromic hearing impairment (NSHI) is the most common sensory defect in humans and is genetically heterogeneous with 15～20% of cases being autosomal dominant (DFNA). DFNA can be caused by mutations in the ACTG1 gene, which encodesγ-actin. Theγ-actin is a cytoplasmic nonmuscle actin, which is a major cytoskeletal protein of the sensory hair cells of the cochlea. A Chinese family with DFNA was identified and characterized. After excluding known genes and genetic loci, linkage was identified with marker D17S928 with a maximum LOD score of 2.17. Haplotype analysis defined the causative gene between D17S928 and D17S784. A novel missense mutation (c.364A>G; p.I122V) was identified in the ACTG1 gene. The mutation co-segregated with the affected individuals in the family and did not exist in unaffected family members and 150 unrelated normal controls. As the families used in previous research were all from Europe and USA, our study partly indicated that the mutations in ACTG1 was a cause of autosomal dominant DFNA in the Chinese family.
第一部分内容是有关遗传性皮肤病的。我们研究了播散性浅表光化性汗孔角化症(DSAP)和寻常型鱼鳞病(IV)。目前为止,DSAP的基因克隆目前还未完成,其病理发生机制也仅限于推测。而寻常型鱼鳞病(IV)发病率很高,有报道称其发病率仅次于感冒,是目前遗传性皮肤病中的研究热点。本论文以我们实验室采集并鉴定的一个DSAP大家系和二个IV家系为基础,对这两种遗传性皮肤病进行了分子遗传学研究。
⑴我们鉴定了一个患有DSAP的中国家系,通过全基因组扫描和连锁分析,首先排除了该家系与已知位点或候选基因的连锁,然后在染色体上1p31.3-p31.1区域,发现了一个新的DSAP连锁位点,在D1S2897获得最大两点LOD值5.09。单倍型分析将该位点精细定位于D1S438和D1S464之间8.2cM,或11.9Mb的范围内。这一结果是迄今为止世界上报道的有关DSAP的第三个遗传位点,对该家系在该位点中的基因进行系统的检测,将有可能发现一个新的DSAP致病基因。对这一课题的进一步研究将有助于阐明DSAP的病理发生机制。
⑵我们鉴定了二个患有IV的中国家系。首先排除了这两个家系与FLG基因和其它鱼鳞病亚型相关疾病致病基因的连锁。通过对其中一个大家系的全基因组扫描和连锁分析,在染色体上10q22.3-q24.2区域得到了最大两点LOD值3.19。单倍型分析将该位点精细定位于D10S569和D10S1709之间20.7cM或20.3Mb的范围内。第二个家系也与该位点连锁,最大LOD值达到3.95。两个独立家系都与该位点连锁的结果,强有力地表明了这一位点内存在一个新的IV致病基因,这是已报道的第二个IV遗传位点,我们的研究为找到新的IV致病基因提供了可能。鉴于目前只有一个IV致病基因被发现,找到一个新的IV致病基因将极大地促进IV的发病机理研究。
第二部分内容是有关遗传性皮肤病的。耳聋严重影响患者的生活,而且发病率很高。非综合征型神经性耳聋(NSHI)是人类最常见的听觉损伤,有很高的遗传异质性,其中15～20%为常染色体显性遗传(DFNA)。ACTG1基因突变可以导致DFNA,它编码的蛋白产物γ-肌动蛋白是一种细胞质的非肌肉肌动蛋白,是耳蜗听觉毛细胞主要的细胞骨架蛋白。
在一个患DFNA的中国人家系中,我们发现致病基因与微卫星多态标记D17S928连锁,进一步的单倍型分析将其定位D17S928和D17S784之间。对该区域内ACTG1基因测序,发现了一新的突变,第122位氨基酸由异亮氨酸变为缬氨酸(c.364A>G;p.I122V)。该突变在家系中与疾病共分离,同时对150个正常对照的RFLP分析也没有发现该突变。鉴于以往有关DFNA研究的家系都来自于欧洲和美洲,我们的结果在一定程度上说明ACTG1基因突变也是导致中国人DFNA的一个重要因素。
Inherited skin disease and nonsyndromic hearing impairment are two important autosomal dominant diseases. In the present study, we have employed the molecular genetic technology, including clinical characterization of large families, linkage mapping of the chromosomal location of the disease causing genes, and mutational analysis, to study the two types of diseases.
The first part of the thesis focuses on inherited skin diseases. We studied disseminated superficial actinic porokeratosis (DSAP) and ichthyosis vulgaris (IV). To date, no specific genes for DSAP have bene definitvely identified, however, there are two genes that have been mapped to chromosomes 12 and 15. In this study, I mapped the third genetic locus for DSAP to chromosome 1. IV has a high prevalence rate, which is ranked the second only after influenza. For IV, there is only one gene, FLG, that has been identified. In this study, I mapped the second genetic locus for IV.
⑴A Chinese DSAP family with autosomal dominant inheritance was identified and clinically characterized. Genome-wide linkage analysis was performed and the known loci or candidate genes were excluded. Further analysis identified a new DSAP locus on chromosome 1p31.3-p31.1 with a maximum two-point LOD score of 5.09 with marker D1S2897. The disease gene was defined within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP (DSAP3). Further mutational analysis of the candidate genes in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP.
⑵Two Chinese families with autosomal dominant IV were clinically and genetically characterized. The FLG gene and other ichthyosis associated genes were first excluded as the disease-causing gene in the two families. The larger family was then characterized by genome-wide linkage analysis to identify a new genetic locus for IV. Significant linkage was identified with markers on chromosome 10q22.3-q24.2 with a maximum LOD score of 3.19. Fine mapping defined the new genetic locus within a 20.7 cM region between markers D10S569 and D10S1709. The second family also showed positive linkage to the same region. The combined maximum LOD score in the two families was 3.95. Identification of linkage in two independent families provides strong genetic evidence that a novel gene for IV is located on chromosome 10q22.3-24.2. Future studies of the candidate genes at the 10q IV locus will identify a specific gene, which will provide insights into the pathogenesis of IV.
The second part of the thesis focuses on genetics of hearing loss. Hearing loss severely affects the quality of life, and has a high prevalence rate. Non-syndromic hearing impairment (NSHI) is the most common sensory defect in humans and is genetically heterogeneous with 15～20% of cases being autosomal dominant (DFNA). DFNA can be caused by mutations in the ACTG1 gene, which encodesγ-actin. Theγ-actin is a cytoplasmic nonmuscle actin, which is a major cytoskeletal protein of the sensory hair cells of the cochlea. A Chinese family with DFNA was identified and characterized. After excluding known genes and genetic loci, linkage was identified with marker D17S928 with a maximum LOD score of 2.17. Haplotype analysis defined the causative gene between D17S928 and D17S784. A novel missense mutation (c.364A>G; p.I122V) was identified in the ACTG1 gene. The mutation co-segregated with the affected individuals in the family and did not exist in unaffected family members and 150 unrelated normal controls. As the families used in previous research were all from Europe and USA, our study partly indicated that the mutations in ACTG1 was a cause of autosomal dominant DFNA in the Chinese family.
引文
[1]杜传书,刘祖洞主编.医学遗传学.第二版.北京:人民卫生出版社, 1983. 896
[2]李伯埙主编.现代实用皮肤病学.第1版.西安:世界图书出版西安公司,2007. 3～11
[3]刘辅仁主编.实用皮肤科学.第3版.北京:人民卫生出版社,2005. 7～15
[4]赵辨主编.临床皮肤病学.第2版.南京:江苏科学技术出版社,2002. 18～23
[5]谢鼎华,杨伟炎主编.耳聋的基础与临床.第1版.长沙:湖南科学技术出版社,2004. 1～5
[6]高荫藻编译.临床耳鼻咽喉组织病理学.第1版.西安:陕西科学技术出版社,1981. 1～19
[7] Hofer D, Ness W, Drenckhahn D. Sorting of actin isoforms in chicken auditory hair cells. J Cell Sci, 1997, 110(6): 765～770
[8] Tilney LG, Egelman EH, DeRosier DJ, et al. Actin filaments, stereocilia, and hair cells of the bird cochlea. II. Packing of actin filaments in the stereocilia and in the cuticular plate and what happens to the organization when the stereocilia are bent. J Cell Biol,1983,96(3): 822～834
[9] DeRosier DJ, Tilney LG. The structure of the cuticular plate, an in vivo actin gel. J Cell Biol,1989,109(1): 2853～2867
[10]钟杰夫主编.图说耳鼻科学.第1版.北京:中国医药科技出版社,1999. 1～12
[11] Bitner-Glindzicz M. Hereditary deafness and phenotyping in humans. Br MedBull,2002,63: 73～94
[12]雷雳.韩德民.遗传性耳聋相关基因研究现状.国外医学遗传学分册,2005,28(4): 227～231
[13] Nance WE. The genetics of deafness. Ment Retard Dev Disabil Res Rev,2003, 9(2): 109～119
[14] Van Camp G, Smith R. Heredirary hearing loss homepage. http://webh01.ua.ac.be/hhh/, July 16, 2006
[15] Kanzaki S, Kawamoto K, Oh SH. From gene indetification to genetherapy [J]. Audiol Neurootol, 2002, 7: 161
[16]贺林.解码生命.第一版.北京:科学出版社, 2000. 84～85
[17]林万明主编. PCR技术操作和应用指南.第一版.北京:人民军医出版社, 1993
[18] J.萨姆布鲁克, D. W.拉塞尔著.分子克隆实验指南.第三版.黄培堂等译.北京:科学出版社, 2002
[19]况少青,张宇舟,陈竺.基因组扫描—遗传病相关基因定位的有力工具.中华医学遗传学, 1997, 14(2): 99～103
[20] Collins F and Galas D. A new five-year plan for the U. S. Human Genome Project. Science, 1993, 262(5130): 43～46
[21]王镭,郑茂波.遗传标记的研究进展.生物技术, 2002, 12(2): 52～54
[22]马洪明,柴建华.人基因组连锁分析和基因定位.生命科学, 1997, 9(1): 19～22
[23]石锐,郭长虹.聚丙烯酰胺凝胶中DNA的银染方法.生物技术, 1998, 8(5): 46～48
[24] Schamroth JM, Zlotogorski A, Gilead L. Porokeratosis of Mibelli: overview and review of literature. Acta Derm Venereol, 1997, 77(3): 207～213
[25] Xia JH, Yang YF, Deng H, et al. Identification of a locus for disseminated superficial actinic porokeratosis at chromosome 12q23.2-24.1. J Invest Dermatol, 2000, 114(6): 1071～1074
[26] Otsuka F, Shima A, Ishibashi Y. Porokeratosis has neoplastic clones in the epidermis: microfluorometric analysis of DNA content of epidermal cell nuclei. J Invest Dermatol, 1989, 92(5): 231～233
[27] Magee JW, McCalmont TH, LeBoit PE. Overexpression of p53 tumor suppressor protein in porokeratosis. Arch Dermatol, 1994, 130(2): 187～190
[28] Urano Y, Sasaki S, Ninomiya Y, et al. Immunohistochemical detection of p53 tumor suppressor protein in porokeratosis. J Dermatol, 1996, 23(5): 365～368
[29] Ninomiya Y, Urano Y, Yoshimoto K, et al. P53 gene mutation analysis in porokeratosis and porokeratosis-associated squamous cell carcinoma. J Dermatol Sci, 1997, 14(3): 173～178
[30] Xia K, Deng H, Xia JH, et al. A novel locus (DSAP2) for disseminated superficial actinic porokeratosis maps to chromosome 15q25.1-26.1. Br J Dermatol, 2002, 147(4): 650～654
[31] Wei S, Yang S, Lin D, et al. A Novel Locus for Disseminated superficial porokeratosis maps to chromosome 18p11.3. J Invest Dermatol, 2004, 123(5): 872～875
[32] Wei SC, Yang S, Li M, et al. Identification of a locus for porokeratosis palmaris et plantaris disseminata to a 6.9-cM region at chromosome 12q24.1-24.2. Br J Dermatol, 2003, 149: 261～267
[33] Zhang Z, Niu Z, Yuan W, et al. Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis. Hum Mutat, 2004, 24(5): 438
[34] Zhang ZH, Niu ZM, Yuan WT, et al. A mutation in SART3 gene in a Chinesepedigree with disseminated superficial actinic porokeratosis. Br J Dermatol, 2005, 152(4): 658～663
[35] Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet, 1984, 36(2): 460～465
[36] Mizukawa Y, Shiohara T. Porokeratosis in patients with hepatitis C virus infection: does hepatitis C virus infection provide a link between porokeratosis and immunosuppression? Br J Dermatol, 1999, 141(1): 163～164
[37] Anzai S, Takeo N, Yamaguchi T, et al. Squamous cell carcinoma in a renal transplant recipient with linear porokeratiosis. J Dermatol, 1999, 26(4): 244～247
[38] Rio B, Magana C, Le Tourneau A, et al. Disseminated superficial porokeratosis after autologous bone marrow transplantation. Bone Marrow Transplant,1997, 19(1): 77～79
[39] Neer EJ. Heterotrimeric G Proteins: Organizers of Transmembrane Signals. Cell, 1995, 80(2): 249～257
[40] Campbell HD, Webb GC, Fountain S, et al. The human PIN1 peptidyl-prolyl cis/trans isomerase gene maps to human chromosome 19p13 and the closely related PIN1L gene to 1p31. Genomics, 1997, 44(2): 157～162
[41] Besta F, Massberg S, Brand K, et al. Role of beta(3)-endonexin in the regulation of NF-kappaB-dependent expression of urokinase-type plasminogen activator receptor. J Cell Sci, 2002, 115(20): 3879～3888
[42] Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene, 2005, 24(50): 7455～7464
[43] Hinterhuber G, Cauza K, Dingelmaier-Hovorka R, et al. Expression of RPE65, a putative receptor for plasma retinol-binding protein, in nonmelanocytic skintumours. Br J Dermatol, 2005, 153(4): 785～789
[44] Airoldi I, Di carlo E, Banelli B, et al. The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies. J Clin Invest, 2004, 113: 1651～1659
[45] Thyss R, Virolle V, Imbert V, et al. NF-kappaB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death. EMBO J, 2005, 24(1): 128～137
[46] Wells RS, Kerr CB. Clinical feature of autosomal dominant and sex-linked ichthyosis in an English population. Br Med J, 1966, 1: 947～950
[47] Lei G, Zhang Y, Hu Y. Investigation on the prevalence of Ichthyosis in Sichuan Province. Chin J Dermatol, 1992, 25: 105～106
[48] Shwayder T, Ott F. All about ichthyosis. Pediatr Clin North Am, 1991, 38(4): 835～857
[49] Ziprkowski L, Feinstein A. A survey of ichthyosis vulgaris in Israel. Br J Dermatol, 1972, 86(1): 1～8
[50] Okulicz JF, Schwartz RA. Hereditary and acquired ichthyosis vulgaris. Int J Dermatol, 2003, 42(2): 95～98
[51] Compton JG, DiGiovanna JJ, Johnston KA, et al. Mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1. Exp Dermatol, 2002, 11(6): 518～526
[52] Zhong W, Cui B, Zhang Y, et al. Linkage analysis suggests a locus of ichthyosis vulgaris on 1q22. J Hum Genet, 2003, 48(7): 390～392
[53] Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet, 2006, 38(3): 337～342
[54] Sandilands A, Terron-Kwiatkowski A, Hull PR, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet, 2007, 39(5): 650～654
[55] Nomura T, Sandilands A, Akiyama M, et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol, 2007, 119(2): 434～440
[56] Zhu M, Yang T, Wei S, et al. Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26). Am J Hum Genet, 2003, 73(5): 1082～1091
[57] Khaitlina SY. Functional specificity of actin isoforms. Int Rev Cytology, 2001, 202: 35～98
[58] Van Wijk E, Krieger E, kemperman MH, et al. A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26). J Med Genet, 2003, 40(12): 879～884
[59] Rendtorff ND, Zhu M, Fagerheim T, et al. A novel missense mutation in ACTG1 causes dominant deafness in a Norwegian DFNA20/26 family, but ACTG1 mutations are not frequent among families with hereditary hearing impairment. Eur J Hum Genet, 2006, 14(10): 1097～1105
[60] Lynch ED, Lee MK, Morrow JE, et al. Nonsyndromic deafness DFNA1associated with mutation of the human homolog of the Drosophila gene diaphanous. Science, 1997, 278(5341): 1315～1318
[61] Carrasquillo MM, Zlotogora J, Barges S, et al. Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations. Hum Mol Genet, 1997, 6(12): 2163～2172
[62] Morell RJ, Kim HJ, Hood LJ, et al. Mutations in the connexin 26 gene (JGB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med, 1998, 339(21): 1500～1505
[63] Abe S, Usami S, Skinkawa H, et al. Prevalent connexin 26 gene (JGB2) mutations in Japanese. J Med Genet, 2000, 37(1): 41～43
[64] Xia JH, Liu CY, Tang BS, et al. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat Genet, 1998, 20(4): 370～373
[65] Liu XZ, Xia XJ, Xu LR, et al. Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. Hum Mol Genet, 2000, 1(9): 63～67
[66] Grifa A, Wagner CA, D’Ambrosio L, et al. Mutations in Gjb6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet, 1999, 23(1): 16～18
[67] Kubisch C, Schroeder BC, Friedrich T, et al. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell, 1999, 96(3): 437～446
[68] Coucke PJ, Van Hauwe P, Kelley PM, et al. Mutations in KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet, 1999, 8(7): 1321～1328
[69] Talebizadeh Z, Kelley Pm, Askew JW, et al. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat, 1999, 14(6): 493～501
[70] Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet, 2000, 93(3): 184～187
[71] Lalwani AK, Goldstein JA, Kelley MJ, et al. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am J Hum Genet, 2000, 67(5): 1121～1128
[72] Donaudy F, Snoeckx R, Pfister M, et al. Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4). Am J Med Genet, 2004, 74(4): 770～776
[73] Yang T, Pfister M, Blin N, et al. Gentics heterogeneity deafness phenotypes linked to DFNA4. Am J Med Genet A, 2005, 139(1): 9～12
[74] Van Laer L, Huizing EH, Verstreken M, et al. Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat Genet, 1998, 20(2): 194～197
[75] Verhoeven K, Van Laer L, Kirschhofer K, et al. Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment. Nat Genet, 1998, 19(1): 60～62
[76] Balciuniene J, Dahl N, Jalonen P, et al. Alpha-tectorin involvement in hearing disabilities: one gene-two phenotypes. Hum Genet, 1999, 105(3): 211～216
[77] Mustapha M, Weil D, chardenoux S, et al. An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non- syndromic deafness, DFNA21. Hum Mol Genet, 1999, 8(3):409～412
[78] Fransen E, Verstreken M, Verhagen WI, et al. High prevalence of symptoms of Meniere’s disease in three families with a mutation in the COCH gene. Hum Mol Genet, 1999, 8(8): 1425～1429
[79] Wayne S, Robertson NG, Declau F, et al. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet, 2001, 10(3): 195～200
[80] Donaudy F, Ferrara A, Exposito L, et al. Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. Am J Hum Genet, 2003, 72(6): 1571～1577
[81] McGuirt WT, Prasad SD, Griffith Aj, et al. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat genet, 1999, 23(4): 413～419
[82] Vahava O, Morell R, Lynch ED, et al. Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science, 1998, 279(5358): 1950～1954
[83] Ng R, Abelson J. Isolation and sequence of the gene for actin in Saccharomyces cerevisiae. Proc Natl Acad Sci USA, 1980, 77(7): 3912～3916
[84] Drubin DG. Actin and actin-binding proteins in yeast. Cell Motil Cytoskeleton, 1990, 15(1): 7～11
[85] Bretscher A, Drees B, Harsay E, et al. What are the basic functions of microfilaments? Insights from studies in budding yeast. J Cell Biol, 1994, 126(4): 821～825
[86] Bryan KE, Wen KK, Zhu M, et al. Effects of human deafnessγ-actin mutations (DFNA20/26) on actin function. J Biol Chem, 2006, 281(29): 20129～20139
[87] Holmes KC, Popp D, Gebhard W, et al. Atomic model of the actin filament.Nature, 1990, 347(6288): 44～49
[88] Feinberg J, Lebart M, Benyamin Y, et al. Localization of a calcium sensitive binding site for gelsolin on actin subdomain I: implication for severing process. Biochem Biophys Res Commun, 1997, 233(1): 61～65
[89] McGough A, Way M, DeRosier D. Determination of the alpha-actinin-binding site on actin filaments by cryoelectron microscopy and image analysis. J Cell Biol, 1994, 126(2): 433～443
[2]李伯埙主编.现代实用皮肤病学.第1版.西安:世界图书出版西安公司,2007. 3～11
[3]刘辅仁主编.实用皮肤科学.第3版.北京:人民卫生出版社,2005. 7～15
[4]赵辨主编.临床皮肤病学.第2版.南京:江苏科学技术出版社,2002. 18～23
[5]谢鼎华,杨伟炎主编.耳聋的基础与临床.第1版.长沙:湖南科学技术出版社,2004. 1～5
[6]高荫藻编译.临床耳鼻咽喉组织病理学.第1版.西安:陕西科学技术出版社,1981. 1～19
[7] Hofer D, Ness W, Drenckhahn D. Sorting of actin isoforms in chicken auditory hair cells. J Cell Sci, 1997, 110(6): 765～770
[8] Tilney LG, Egelman EH, DeRosier DJ, et al. Actin filaments, stereocilia, and hair cells of the bird cochlea. II. Packing of actin filaments in the stereocilia and in the cuticular plate and what happens to the organization when the stereocilia are bent. J Cell Biol,1983,96(3): 822～834
[9] DeRosier DJ, Tilney LG. The structure of the cuticular plate, an in vivo actin gel. J Cell Biol,1989,109(1): 2853～2867
[10]钟杰夫主编.图说耳鼻科学.第1版.北京:中国医药科技出版社,1999. 1～12
[11] Bitner-Glindzicz M. Hereditary deafness and phenotyping in humans. Br MedBull,2002,63: 73～94
[12]雷雳.韩德民.遗传性耳聋相关基因研究现状.国外医学遗传学分册,2005,28(4): 227～231
[13] Nance WE. The genetics of deafness. Ment Retard Dev Disabil Res Rev,2003, 9(2): 109～119
[14] Van Camp G, Smith R. Heredirary hearing loss homepage. http://webh01.ua.ac.be/hhh/, July 16, 2006
[15] Kanzaki S, Kawamoto K, Oh SH. From gene indetification to genetherapy [J]. Audiol Neurootol, 2002, 7: 161
[16]贺林.解码生命.第一版.北京:科学出版社, 2000. 84～85
[17]林万明主编. PCR技术操作和应用指南.第一版.北京:人民军医出版社, 1993
[18] J.萨姆布鲁克, D. W.拉塞尔著.分子克隆实验指南.第三版.黄培堂等译.北京:科学出版社, 2002
[19]况少青,张宇舟,陈竺.基因组扫描—遗传病相关基因定位的有力工具.中华医学遗传学, 1997, 14(2): 99～103
[20] Collins F and Galas D. A new five-year plan for the U. S. Human Genome Project. Science, 1993, 262(5130): 43～46
[21]王镭,郑茂波.遗传标记的研究进展.生物技术, 2002, 12(2): 52～54
[22]马洪明,柴建华.人基因组连锁分析和基因定位.生命科学, 1997, 9(1): 19～22
[23]石锐,郭长虹.聚丙烯酰胺凝胶中DNA的银染方法.生物技术, 1998, 8(5): 46～48
[24] Schamroth JM, Zlotogorski A, Gilead L. Porokeratosis of Mibelli: overview and review of literature. Acta Derm Venereol, 1997, 77(3): 207～213
[25] Xia JH, Yang YF, Deng H, et al. Identification of a locus for disseminated superficial actinic porokeratosis at chromosome 12q23.2-24.1. J Invest Dermatol, 2000, 114(6): 1071～1074
[26] Otsuka F, Shima A, Ishibashi Y. Porokeratosis has neoplastic clones in the epidermis: microfluorometric analysis of DNA content of epidermal cell nuclei. J Invest Dermatol, 1989, 92(5): 231～233
[27] Magee JW, McCalmont TH, LeBoit PE. Overexpression of p53 tumor suppressor protein in porokeratosis. Arch Dermatol, 1994, 130(2): 187～190
[28] Urano Y, Sasaki S, Ninomiya Y, et al. Immunohistochemical detection of p53 tumor suppressor protein in porokeratosis. J Dermatol, 1996, 23(5): 365～368
[29] Ninomiya Y, Urano Y, Yoshimoto K, et al. P53 gene mutation analysis in porokeratosis and porokeratosis-associated squamous cell carcinoma. J Dermatol Sci, 1997, 14(3): 173～178
[30] Xia K, Deng H, Xia JH, et al. A novel locus (DSAP2) for disseminated superficial actinic porokeratosis maps to chromosome 15q25.1-26.1. Br J Dermatol, 2002, 147(4): 650～654
[31] Wei S, Yang S, Lin D, et al. A Novel Locus for Disseminated superficial porokeratosis maps to chromosome 18p11.3. J Invest Dermatol, 2004, 123(5): 872～875
[32] Wei SC, Yang S, Li M, et al. Identification of a locus for porokeratosis palmaris et plantaris disseminata to a 6.9-cM region at chromosome 12q24.1-24.2. Br J Dermatol, 2003, 149: 261～267
[33] Zhang Z, Niu Z, Yuan W, et al. Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis. Hum Mutat, 2004, 24(5): 438
[34] Zhang ZH, Niu ZM, Yuan WT, et al. A mutation in SART3 gene in a Chinesepedigree with disseminated superficial actinic porokeratosis. Br J Dermatol, 2005, 152(4): 658～663
[35] Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet, 1984, 36(2): 460～465
[36] Mizukawa Y, Shiohara T. Porokeratosis in patients with hepatitis C virus infection: does hepatitis C virus infection provide a link between porokeratosis and immunosuppression? Br J Dermatol, 1999, 141(1): 163～164
[37] Anzai S, Takeo N, Yamaguchi T, et al. Squamous cell carcinoma in a renal transplant recipient with linear porokeratiosis. J Dermatol, 1999, 26(4): 244～247
[38] Rio B, Magana C, Le Tourneau A, et al. Disseminated superficial porokeratosis after autologous bone marrow transplantation. Bone Marrow Transplant,1997, 19(1): 77～79
[39] Neer EJ. Heterotrimeric G Proteins: Organizers of Transmembrane Signals. Cell, 1995, 80(2): 249～257
[40] Campbell HD, Webb GC, Fountain S, et al. The human PIN1 peptidyl-prolyl cis/trans isomerase gene maps to human chromosome 19p13 and the closely related PIN1L gene to 1p31. Genomics, 1997, 44(2): 157～162
[41] Besta F, Massberg S, Brand K, et al. Role of beta(3)-endonexin in the regulation of NF-kappaB-dependent expression of urokinase-type plasminogen activator receptor. J Cell Sci, 2002, 115(20): 3879～3888
[42] Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene, 2005, 24(50): 7455～7464
[43] Hinterhuber G, Cauza K, Dingelmaier-Hovorka R, et al. Expression of RPE65, a putative receptor for plasma retinol-binding protein, in nonmelanocytic skintumours. Br J Dermatol, 2005, 153(4): 785～789
[44] Airoldi I, Di carlo E, Banelli B, et al. The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies. J Clin Invest, 2004, 113: 1651～1659
[45] Thyss R, Virolle V, Imbert V, et al. NF-kappaB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death. EMBO J, 2005, 24(1): 128～137
[46] Wells RS, Kerr CB. Clinical feature of autosomal dominant and sex-linked ichthyosis in an English population. Br Med J, 1966, 1: 947～950
[47] Lei G, Zhang Y, Hu Y. Investigation on the prevalence of Ichthyosis in Sichuan Province. Chin J Dermatol, 1992, 25: 105～106
[48] Shwayder T, Ott F. All about ichthyosis. Pediatr Clin North Am, 1991, 38(4): 835～857
[49] Ziprkowski L, Feinstein A. A survey of ichthyosis vulgaris in Israel. Br J Dermatol, 1972, 86(1): 1～8
[50] Okulicz JF, Schwartz RA. Hereditary and acquired ichthyosis vulgaris. Int J Dermatol, 2003, 42(2): 95～98
[51] Compton JG, DiGiovanna JJ, Johnston KA, et al. Mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1. Exp Dermatol, 2002, 11(6): 518～526
[52] Zhong W, Cui B, Zhang Y, et al. Linkage analysis suggests a locus of ichthyosis vulgaris on 1q22. J Hum Genet, 2003, 48(7): 390～392
[53] Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet, 2006, 38(3): 337～342
[54] Sandilands A, Terron-Kwiatkowski A, Hull PR, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet, 2007, 39(5): 650～654
[55] Nomura T, Sandilands A, Akiyama M, et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol, 2007, 119(2): 434～440
[56] Zhu M, Yang T, Wei S, et al. Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26). Am J Hum Genet, 2003, 73(5): 1082～1091
[57] Khaitlina SY. Functional specificity of actin isoforms. Int Rev Cytology, 2001, 202: 35～98
[58] Van Wijk E, Krieger E, kemperman MH, et al. A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26). J Med Genet, 2003, 40(12): 879～884
[59] Rendtorff ND, Zhu M, Fagerheim T, et al. A novel missense mutation in ACTG1 causes dominant deafness in a Norwegian DFNA20/26 family, but ACTG1 mutations are not frequent among families with hereditary hearing impairment. Eur J Hum Genet, 2006, 14(10): 1097～1105
[60] Lynch ED, Lee MK, Morrow JE, et al. Nonsyndromic deafness DFNA1associated with mutation of the human homolog of the Drosophila gene diaphanous. Science, 1997, 278(5341): 1315～1318
[61] Carrasquillo MM, Zlotogora J, Barges S, et al. Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations. Hum Mol Genet, 1997, 6(12): 2163～2172
[62] Morell RJ, Kim HJ, Hood LJ, et al. Mutations in the connexin 26 gene (JGB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med, 1998, 339(21): 1500～1505
[63] Abe S, Usami S, Skinkawa H, et al. Prevalent connexin 26 gene (JGB2) mutations in Japanese. J Med Genet, 2000, 37(1): 41～43
[64] Xia JH, Liu CY, Tang BS, et al. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat Genet, 1998, 20(4): 370～373
[65] Liu XZ, Xia XJ, Xu LR, et al. Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. Hum Mol Genet, 2000, 1(9): 63～67
[66] Grifa A, Wagner CA, D’Ambrosio L, et al. Mutations in Gjb6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet, 1999, 23(1): 16～18
[67] Kubisch C, Schroeder BC, Friedrich T, et al. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell, 1999, 96(3): 437～446
[68] Coucke PJ, Van Hauwe P, Kelley PM, et al. Mutations in KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet, 1999, 8(7): 1321～1328
[69] Talebizadeh Z, Kelley Pm, Askew JW, et al. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat, 1999, 14(6): 493～501
[70] Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet, 2000, 93(3): 184～187
[71] Lalwani AK, Goldstein JA, Kelley MJ, et al. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am J Hum Genet, 2000, 67(5): 1121～1128
[72] Donaudy F, Snoeckx R, Pfister M, et al. Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4). Am J Med Genet, 2004, 74(4): 770～776
[73] Yang T, Pfister M, Blin N, et al. Gentics heterogeneity deafness phenotypes linked to DFNA4. Am J Med Genet A, 2005, 139(1): 9～12
[74] Van Laer L, Huizing EH, Verstreken M, et al. Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat Genet, 1998, 20(2): 194～197
[75] Verhoeven K, Van Laer L, Kirschhofer K, et al. Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment. Nat Genet, 1998, 19(1): 60～62
[76] Balciuniene J, Dahl N, Jalonen P, et al. Alpha-tectorin involvement in hearing disabilities: one gene-two phenotypes. Hum Genet, 1999, 105(3): 211～216
[77] Mustapha M, Weil D, chardenoux S, et al. An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non- syndromic deafness, DFNA21. Hum Mol Genet, 1999, 8(3):409～412
[78] Fransen E, Verstreken M, Verhagen WI, et al. High prevalence of symptoms of Meniere’s disease in three families with a mutation in the COCH gene. Hum Mol Genet, 1999, 8(8): 1425～1429
[79] Wayne S, Robertson NG, Declau F, et al. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet, 2001, 10(3): 195～200
[80] Donaudy F, Ferrara A, Exposito L, et al. Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. Am J Hum Genet, 2003, 72(6): 1571～1577
[81] McGuirt WT, Prasad SD, Griffith Aj, et al. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat genet, 1999, 23(4): 413～419
[82] Vahava O, Morell R, Lynch ED, et al. Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science, 1998, 279(5358): 1950～1954
[83] Ng R, Abelson J. Isolation and sequence of the gene for actin in Saccharomyces cerevisiae. Proc Natl Acad Sci USA, 1980, 77(7): 3912～3916
[84] Drubin DG. Actin and actin-binding proteins in yeast. Cell Motil Cytoskeleton, 1990, 15(1): 7～11
[85] Bretscher A, Drees B, Harsay E, et al. What are the basic functions of microfilaments? Insights from studies in budding yeast. J Cell Biol, 1994, 126(4): 821～825
[86] Bryan KE, Wen KK, Zhu M, et al. Effects of human deafnessγ-actin mutations (DFNA20/26) on actin function. J Biol Chem, 2006, 281(29): 20129～20139
[87] Holmes KC, Popp D, Gebhard W, et al. Atomic model of the actin filament.Nature, 1990, 347(6288): 44～49
[88] Feinberg J, Lebart M, Benyamin Y, et al. Localization of a calcium sensitive binding site for gelsolin on actin subdomain I: implication for severing process. Biochem Biophys Res Commun, 1997, 233(1): 61～65
[89] McGough A, Way M, DeRosier D. Determination of the alpha-actinin-binding site on actin filaments by cryoelectron microscopy and image analysis. J Cell Biol, 1994, 126(2): 433～443