Abstract
Hearing impairment is a frequent handicap that can have profound social and psychological effects. Depending on which part of the hearing system that is damaged, conductive and sensorineural hearing loss can be distinguished. Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, which usually results in a conductive hearing loss due to fixation of the stapes footplate, although sensorineural hearing loss also may occur. Clinical otosclerosis has a prevalence of 0.3 0.4% among white adults. Although there are families with autosomal dominantly inherited otosclerosis, it is a complex disease in most cases, involving genetic as well as environmental factors. However, none of these factors are currently known. This lack of knowledge is the main obstacle to improve the morbidity involved by this disease. Until now three loci for autosomal dominant otosclerosis, respectively OTSC1 (15q25-26), OTSC2 (7q34-36) and OTSC3 (6p21.2-22.3), have been found, but the genes have not been identified yet. In addition, most families don't show linkage to OTSC1, OTSC2 and OTSC3 indicating that there must be additional loci for otosclerosis.
The specific aim of the study is to identify novel otosclerosis genes by conventional parametric linkage analysis as well as by non-parametric linkage analysis. Parametric linkage analysis will be carried out on two large autosomal dominant otosclerosis families. First a genome search, in cooperation with the MDC-Gene Mapping Centre of Berlin, will be performed in the two families to localize the otosclerosis genes. The resulting candidate regions will be refined by analysis of additional markers. Subsequently, mutation analysis will be performed on candidate genes in these regions to identify the otosclerosis genes. Computer analysis of the DNA sequence and analysis of the expression pattern will help to identify a possible function for the protein.
A second part of the project aims at the identification of novel otosclerosis genes by non-parametric linkage analysis using a large collection of small families and association study on unrelated patients. The main method of non-parametric linkage will be affected sib pair analysis. A total genome scan will identify genomic regions that contain genes involved in the etiology of otosclerosis. In these regions potential candidate genes will be selected. These genes will be tested in an association study using Single Nucleotide Polymorphism (SNP) genotyping in a set of unrelated patients and matched controls. Genes showing association will be sequenced in order to identify the disease-causing variant. Using these methods, we aim to identify one or more genes for otosclerosis.
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