Disease relevance of SIX5

• Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy [1].
• Heterozygous loss of SIX5 in mice causes cataracts and cardiac conduction disease, and homozygous loss also leads to sterility and decreased testicular mass, reminiscent of DM1 in humans [2].

High impact information on SIX5

• Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder [3].
• Together, these results demonstrate that CTG-repeat expansions can suppress local gene expression and implicate DMAHP in DM pathogenesis [4].
• Here we report that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene [4].
• At both loci, expansion is associated with altered chromatin, aberrant methylation, and suppressed expression of the adjacent FMR1 and DMAHP genes, implicating epigenetic mediation of these genetic diseases [5].
• The repeat expansion suppresses the expression of the homeobox gene SIX5 [6].

Biological context of SIX5

• Finally, a whole genome PCR-based screen was used to identify genomic DNA sequences to which SIX5 binds, as an initial stage in the identification of genes regulated by SIX5 [7].
• Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy [8].
• SIX5 mRNA was not detected in normal ovarian epithelial tissue at any of the times studied during the menstrual cycle [9].
• Moreover, a variety of data have implicated human SIX5 dysfunction as a contributor to myotonic dystrophy type 1 (DM1), a condition characterized by a number of pathologies including muscle defects and testicular atrophy [10].
• In this study, we found that muscle contractile properties, electromyographic insertional activity, and muscle histology were normal in SIX5 deficient mice [2].

Anatomical context of SIX5

• SIX5 transcripts were detected in the adult corneal epithelium and endothelium, lens epithelium, ciliary body epithelia, cellular layers of the retina and the sclera [1].
• We have found that the level of the DM-associated allele in the cytoplasm of DM cell lines is reduced by 20-50% compared with the wild-type allele, similar to the level of reduction found for SIX5 in allele-specific analysis [11].
• CONCLUSIONS: SIX5 expression is present in the normal epithelium throughout most of the female reproductive tract, suggesting it may have a role in maintaining epithelial differentiation in these tissues [9].
• RESULTS: Expression of SIX5 mRNA was demonstrated in normal Fallopian tube epithelium and normal endocervical epithelium [9].
• In 31 of 37 borderline epithelial ovarian tumours (84%), SIX5 expression was found in the epithelial cells [9].

Other interactions of SIX5

• SIX5 is a homeodomain gene located just downstream of the repeat, and myotonic dystrophy WD protein (DMWD) is located close upstream of DMPK [12].
• The mammalian SIX5/SIX4 gene pair is likely to be involved in the development of mesodermal structures [10].

Analytical, diagnostic and therapeutic context of SIX5

• Using a quantitative fluorescent RT-PCR assay, we tested allele-specific accumulation of DMAHP/SIX5 transcripts in both total and poly(A)+pools [13].
• Furthermore, real-time PCR analysis showed reduced SIX5 expression and increased expression of the Ca(2+)-activated K(+) channel SK3 in the DM1 cells [14].
• Endogenous SIX5 migrated in SDS-PAGE with an apparent M(r) of 100 kDa and was present at similar levels in all foetal tissues and cell lines tested [15].
• However, SIX5 transcripts are known to be present at very low levels in cells and no study has yet convincingly demonstrated detection of endogenous SIX5 protein by Western blotting or immunolocalisation [15].

References