To collect data on the prevalence of mutations in the CX26 gene in individuals with non-syndromic hearing impairment (NSSNHI) from various European populations. The locations of twenty-eight genes causing autosomal recessive non-syndromal sensorineural hearing impairment (NSSNHI) have been mapped over the last seven years. The first of these loci (DFNB1) accounts for a high proportion (about 75%) of congenital/early childhood onset NSSNHI. The CX26 gene which encodes the gap junction protein beta-2 (GJB2) has been shown to cause hearing impairment at the DFNB1 locus. A single mutation consisting of a deletion of single guanine (G) nucleotide within six Gs at positions 30 to 35 of CX26, variably known as 30 or 35delG, has been found to account for the majority (>60%) of mutations in CX26 in persons of Western European origin. Now, the goal is to collect data on the type and prevalence of mutations in the CX26 gene in persons with NSSNHI from various European populations.

To measure the frequency and range of mutations in myosin VII A and usherin in individuals with Usher syndrome. Usher syndrome being an autosomal recessive disorder is the most common condition that involves both hearing and vision problems. Usher syndrome occurs with a prevalence of 6-8/100,000 in most countries where the condition has been studied. Usher syndrome is the most frequent cause of acquired deafblindness. The diagnosis of Usher syndrome is often made late in life (young adulthood). This late diagnosis has large implications on the affected people and their families. Since retinitis pigmentosa in Usher syndrome is progressive the rehabilitation in terms of communication and education becomes extremely important once the diagnosis is made. The objective is to ensure that future Usher syndrome patients will get as early as possible proper investigation and thus rehabilitation. Another objective is to ensure proper genetic counselling to families.

To develop exploitable pathogenic models of aminoglycoside ototoxicity and other forms of mitochondrial deafness. Mitochondrial DNA mutations are among the first genetic lesions shown to be causally associated with both syndromic and non-syndromic forms of deafness. In particular, a relatively common point mutation (A1555G) in the mitochondrial gene for small subunit rRNA has been shown to predispose to aminoglycoside ototoxicity in different ethnic groups. Aminoglycoside antibiotics, which are commonly used in clinical practice, impair the accuracy of protein synthesis on bacterial-type ribosomes. Mitochondrial ribosomes are closely related to those from bacteria, but are relatively immune to the effects of aminoglycosides. However, the A1555G mutation appears to alter the structure of the mitochondrial ribosome so that it become susceptible to these agents. Why the cells of the auditory system are especially vunerable to this remains unexplained, therefore a pathological model is urgently needed for this, as for other forms of mitochondrial deafness. Two kinds of pathological models will be developed to study mitochondrial deafness: firstly cell-culture models, based on the rho-zero cybrid system, secondly whole organism models, using the fruit fly Drosophila. The Drosophila model that will be exploited has a mutation in a gene (tko) for a component of the mitochondrial protein synthetic apparatus, which creates a phenotype with many of the features of mitochondrially determined hearing impairment in humans. Using the range of genetic, cytological and physiological methods now available in this organism, the mutant will be investigated to determine the precise molecular and cellular mechanisms that cause the hearing impairment. Various genetic and pharmacological approaches will be tested for their ability to correct the defect. Additional mutations in the same gene will be engineered, that are predicted to mimic aminoglycoside ototoxicity in humans. These models will be investigated by similar approaches. Four key objectives of the work will be: (1) to define the molecular phenotypes of the most important deafness-associated mtDNA mutations; (2) to determine the effects of nuclear genetic and developmental background on the expression of these phenotypes in cultured cells; (3) to develop an animal model of aminoglycoside-associated mitochondrial deafness; and (4) to define the precise physiological consequences for mechanoreceptor function of a mitochondrial translational deficit, via exploitation of the Drosophila model.

To establish phenotypic criteria for recognising subgroups of non-syndromic hearing impairment. Over a 100 genes are estimated to be involved in non sindromic genetic hearing impairment. In the last decade about 60 loci have been found and 19 genes have been already cloned. Each gene may present several mutations that can possibly be cause of disease. This can give reason of the great clinical and genetical heterogeneity that has been described. This can also be due to the interference of environmental factors. Occurrence of each disorder is rare per se, although hearing impairment of a genetic nature accounts for about 50% of cases. As it is, a diagnostic screening would be too costly and too time consuming, therefore it is important to find clinical correlates that can target a more specific diagnosis. Many genes are still unknown and little is known about corresponding gene products and their function in the cochlea. At present the clinical presentation described to the discovered loci associated with hearing impairment refers to loci which represent wide segments of DNA that may contain one or more abnormal genes and give no information on the nature of the gene involved or its function. Another bias in associating a genotype to its clinical correlates can derive from the fact that the phenotype associated to an identified locus derives from the analysis of one or few families with positive linkage to the locus. Therefore, given the high degree of variability either due to penetrance, ageing or environmental causes that has been observed even within the same familial group, it is likely that the phenotypes described will change as more cases are diagnosed with a specific disorder. Often geneticists tend to give general information about the clinical presentation of a disorder, while in non syndromic hearing impairment it is important a thorough clinical investigation to look for clues to distinguish the different conditions. Lastly, the clinical tests available for diagnosis are not specific. It is therefore of great importance a continuous update, surveillance and strict collaboration among researchers on this aspect in order to obtain clues to a more sensitive and accurate diagnosis and counselling.
     The main goal is the collection of results from the other groups, the surveillance on all publications in the field and when necessary the request to the authors of a thorough description of the phenotype. The analysis of the correlation between genotype and clinical presentation will be conducted on the databases that each clinical or genetical center of this network will provide, in order to establish, if possible, phenotypic criteria for recognising subgroups of non-syndromic hearing impairment.
     This effort will involve an evaluation of genotype/phenotype association of non-syndromic hearing impairment (NSHI), in particular for Cx26 different mutations (the most frequent cause of hereditary hearing impairment) and for mitochondrial disorders associated with hearing impairment. At now, no epidemiological data exist and prevalence data vary considerably depending on the criteria applied in the study mainly due to the high number of possible genes causing the different conditions as well as for the clinical and genetical heterogeneity, therefore no cohort studies can be conducted at the moment, since there isn't the possibility to screen the population for different genotypes. The network will make it possible to collect as much information as possible that will allow some type of epidemiological analysis. Furthermore, it will give guidelines directing both clinicians and geneticists to establish homogeneous citeria, collaborations that will help obtaining useful information to be applied to routine patient clinic. This will favour the merging of results from different EU countries and finally improve diagnosis and better counselling. The Hereditary Hearing Loss homepage will be updated and a new section, describing the project results, will be implemented and regularly updated as progress in the field proceeds.

To define the specific psychosocial impact of genetic hearing impairment on affected individuals and their families. The specific psychosocial impact of genetic hearing impairment have not been systematically investigated till now. In general Audiologists and those concerned with psycho-social aspects of hearing impairment have not considered genetic factors separately from other causes of hearing impairment in this context. Geneticists, on the other hand, as a basis of their genetic counselling, have not specifically separated the consequences of hearing impairment from that of other genetically determined disablements. In addition, no thought has been given to the consequences of genetic hearing impairment on the individuals, and those around them, in the different societies existing in Europe. Now, with new developments in molecular genetics (see WP2, WP3 and WP4), more precise information can be given to patients as concerning the aetiology of their or their childrens' impairment. This will play an increasing role which can be made more precise from a behavioural standpoint once the expected psychosocial effects will be known.
     The aim will be to clarify the specific effects that knowledge of a genetic aetiology for their hearing impairment has for affected individuals and their families.
     The information needed to improve the genetic counselling in this field will be obtained initially by a review of the literature which will also highlight the deficiencies in our knowledge. From this, the group will develop three questionnaires aimed at bridging these gaps. The first will be sent to professionals, particularly audiological clinicians and genetic counsellors in this field. The second will be administered to patient associates brought together by workpackage 7 and the third will be sent to individual patients of the clinicians working in the different components of GENDEAF.
     The questionnaires will be formulated by members MB27, MB32 and MB33 who all have extensive experience in questionnaire development and analysis. They will be formulated on the basis of the literature review and focus groups comprising the clinicians and genetic counsellors in the different WPs together with a range of patient groups and patients highlighted by WP7.
     Models of the development of psychosocial consequences of genetic hearing impairment will be developed separately for the three broad types of impairment being considered: congenital severe/profound hearing impairment; late onset dominant genetic hearing impairment and deaf blindness. The models will be based on the World Health Organisations "International Classification of Functioning Disability and Health - ICIDH-2 (2000) of which the final and definitive version will be published in mid 2001, and for which the pre-final version is currently available.
     This model highlights the role of environmental (human and societal) and personal factors in the development of the 'Activity Limitation' and 'Participation Restriction' of the individual. The way in which these interact with the underlying impairment and how negative effects can be reversed will be highlighted in the final models. These models will then serve as a basis for improved genetic counselling and to improve the understanding of their condition by individuals with the conditions concerned.

To facilitate communication between the research and hearing impaired communities (patients, families and their associations). The main objective is to create a network between associations and between associations and researchers for the exchange of information with regard to research advances, but also patient's needs and expectations. Patients and patients' families information is essential for them to be open to research advances and therefore contribute to it actively. A bulletin will be published that will be targeted to patients, their families and medical personnel involved in genetical hearing impairment. Besides English, the bulletin will be translated also in Swedish, French, German, and Italian language.
     The wording of the bulletin has to be in a lay language, i.e. in a form that may be understood by non scientific and non medical people.
     The bulletin will also be published on Internet in the different languages. The network objective is to inspire such initiatives throughout Europe. The consortium will collaborate with any other organisation which will request the authorisation for translating it into other languages.


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