X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats

We have, identified a novel gene, transducin (beta)-like 1 (TBL1), in the X p22.3 genomic region, that shows high homology with members of the WD-40-re peat protein family. The gene Contains 18 exons: spanning similar to 150 kb of the genomic region adjacent to the ocular albinism gene (OA1) on the te lomeric side. However, unlike OA1, TBL1 is' transcribed from telomere. to c entromere. Northern analysis indicates that TBL1 is ubiquitously expressed, with two transcripts of similar to 2.1 kb and 6.0 kb. The open reading fra me encodes a 526-amino acid protein, which shows the presence of six beta-t ransducin repeats (WD-40 motif) in the C-terminal domain. The homology with known beta-subunits of G proteins and other WD-40-repeat containing protei ns-is restricted to the WD-40 motif. Genomic analysis revealed that the gen e is either partly or entirely deleted in patients carrying Xp22.3 terminal deletions, The complexity of the contiguous gene-syndrome phenotype shared by these patients depends on the number of known disease genes involved in the deletions; Interestingly, one patient carrying a microinterstitial del etion involving the 3' portion of both TBL1 and OA1 shows the OA1 phenotype associated with X-linked late-onset sensorineural deafness. We postulate a n involvement of TBL1 in the pathogenesis of the ocular albinism with late- onset sensorineural deafness phenotype.