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 Xp22.3 genomic region, that shows high homology with members of the WD-40-repeat protein family. The gene contains 18 exons spanning approximately 150 kb of the genomic region adjacent to the ocular albinism gene (OA1) on the telomeric side. However, unlike OA1, TBL1 is transcribed from telomere to centromere. Northern analysis indicates that TBL1 is ubiquitously expressed, with two transcripts of approximately 2.1 kb and 6.0 kb. The open reading frame encodes a 526-amino acid protein, which shows the presence of six beta-transducin repeats (WD-40 motif) in the C-terminal domain. The homology with known beta-subunits of G proteins and other WD-40-repeat containing proteins is restricted to the WD-40 motif. Genomic analysis revealed that the gene 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 deletion involving the 3' portion of both TBL1 and OA1 shows the OA1 phenotype associated with X-linked late-onset sensorineural deafness. We postulate an involvement of TBL1 in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype.
D000595:Amino Acid Sequence; D001483:Base Sequence; D018076:DNA, Complementary; D003638:Deafness / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D015293:Transducin / Q000235:genetics*; D014960:X Chromosome