ABSENCE OF TRANSCRIPTIONAL REPRESSION LEADS TO SENSORINEURAL DEAFNESS

People affected by ocular albinism with late-onset sensorineural deafness (OASD) are characterized by ocular albinism, translucent pale blue irides, reduction in retinal pigment, with severe visual impairment, skin hyperpigmentation and progressive loss of hearing during the fourth or fifth decade of their life. The OASD is an X-linked recessive disorder, meaning that only the male part of the population can be affected. Recently, a new gene, TBL1, has been cloned and mapped in the region of the X-chromosome that is genetically related to OASD. In the same region is also located the gene responsible for the classical form of ocular albinism, OA1. The fact that, in one patient, it has been found association between OASD and a partial deletion of both the TBL1 gene and the OA1 gene, suggests that TBL1 could play a direct role in the progressive loss of hearing, that represents the distinctive feature of this pathology compared to other forms of ocular albinism. Previous observations relates TBL1 to a complex of co-repressor factors, NCoR/SMRT and histone deacetilase-3, used in the regulation of transcription by different transcription factors. This suggests that TBL1 could also function as a repressor molecule. The lack of repression, due to TBL1 absence or malfunctioning, could then be the cause of deafness in the OASD disorder. In this project I propose to study, both in vivo and in vitro, the role of TBL1, with particular attention to the auditory system, in order to clearly define if TBL1 is directly involved in the development of hearing impairment and in order to understand the specific molecular mechanism of TBL1 activity.