Elucidation of the Molecular Genetic Basis of Inherited Hearing Impairment.

Hearing loss is the most common sensory disorder in the human population. It affects 0.1% of all young children and by the age of 70, 30% of the population suffers from hearing loss greater than 40 dB. When early onset hearing loss is inherited, 70% is classified as nonsyndromic and 30% as syndromic. Nonsyndromic hearing loss is further subdivided by its mode of inheritance; ~77% of the cases are autosomal recessive (DFNB), ~22% are autosomal dominant (DFNA) and ~1% are X-linked (DFN). Eighty nonsyndromic hearing loss loci have been described so far, but new loci are continuously found. For approximately half of the loci the genetic defect responsible for the hearing loss has been identified. Recently several new strategies have been developed to elucidate the genetic defect for the remaining loci. One of these new strategies, the construction and analysis of a cDNA library, is described in chapter two. DFNA5, is characterised by high frequency hearing loss caused by a mutation in the DFNA5 gene. The second Dutch family with DFNA5 is described in chapter three. The hearing impairment in this family is caused by a novel mutation in DFNA5. The mutation likely results in a deleterious gain of function of the protein in the inner ear. Another form of high frequency hearing loss, DFNA11, is associated with a mutation in the MYO7A gene. In chapter 4 a Dutch family with DFNA11 is described in which hearing impairment segregates with a novel mutation in MYO7A. The nucleotide change is predicted to lead to an amino acid change in the motor domain, causing severe effects on the function of the myosin VIIA protein. Usher syndrome is a form of syndromic hearing loss that is characterized by various degrees of congenital hearing loss and of loss of eyesight through progressive retinitis pigmentosa. Chapter 5 describes the identification of mutations in VLGR1 in patients suffering from Usher syndrome type IIC