| 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. |
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