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Gene Review

SIX5  -  SIX homeobox 5

Homo sapiens

Synonyms: BOR2, DM locus-associated homeodomain protein, DMAHP, Homeobox protein SIX5, Sine oculis homeobox homolog 5
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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].


  1. Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy. Winchester, C.L., Ferrier, R.K., Sermoni, A., Clark, B.J., Johnson, K.J. Hum. Mol. Genet. (1999) [Pubmed]
  2. Myotonia and muscle contractile properties in mice with SIX5 deficiency. Personius, K.E., Nautiyal, J., Reddy, S. Muscle Nerve (2005) [Pubmed]
  3. Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Klesert, T.R., Cho, D.H., Clark, J.I., Maylie, J., Adelman, J., Snider, L., Yuen, E.C., Soriano, P., Tapscott, S.J. Nat. Genet. (2000) [Pubmed]
  4. Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP. Klesert, T.R., Otten, A.D., Bird, T.D., Tapscott, S.J. Nat. Genet. (1997) [Pubmed]
  5. Fragile-X syndrome and myotonic dystrophy: parallels and paradoxes. Tapscott, S.J., Klesert, T.R., Widrow, R.J., Stöger, R., Laird, C.D. Curr. Opin. Genet. Dev. (1998) [Pubmed]
  6. Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1. Sato, S., Nakamura, M., Cho, D.H., Tapscott, S.J., Ozaki, H., Kawakami, K. Hum. Mol. Genet. (2002) [Pubmed]
  7. Functional analysis of the homeodomain protein SIX5. Harris, S.E., Winchester, C.L., Johnson, K.J. Nucleic Acids Res. (2000) [Pubmed]
  8. Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy. Frisch, R., Singleton, K.R., Moses, P.A., Gonzalez, I.L., Carango, P., Marks, H.G., Funanage, V.L. Mol. Genet. Metab. (2001) [Pubmed]
  9. Expression of a homeobox gene (SIX5) in borderline ovarian tumours. Winchester, C., Robertson, S., MacLeod, T., Johnson, K., Thomas, M. J. Clin. Pathol. (2000) [Pubmed]
  10. Drosophila homolog of the myotonic dystrophy-associated gene, SIX5, is required for muscle and gonad development. Kirby, R.J., Hamilton, G.M., Finnegan, D.J., Johnson, K.J., Jarman, A.P. Curr. Biol. (2001) [Pubmed]
  11. Myotonic dystrophy is associated with a reduced level of RNA from the DMWD allele adjacent to the expanded repeat. Alwazzan, M., Newman, E., Hamshere, M.G., Brook, J.D. Hum. Mol. Genet. (1999) [Pubmed]
  12. Real-time RT-PCR for CTG repeat-containing genes. Eriksson, M. Methods Mol. Biol. (2004) [Pubmed]
  13. Myotonic dystrophy: tissue-specific effect of somatic CTG expansions on allele-specific DMAHP/SIX5 expression. Korade-Mirnics, Z., Tarleton, J., Servidei, S., Casey, R.R., Gennarelli, M., Pegoraro, E., Angelini, C., Hoffman, E.P. Hum. Mol. Genet. (1999) [Pubmed]
  14. Increased SK3 expression in DM1 lens cells leads to impaired growth through a greater calcium-induced fragility. Rhodes, J.D., Monckton, D.G., McAbney, J.P., Prescott, A.R., Duncan, G. Hum. Mol. Genet. (2006) [Pubmed]
  15. Characterisation of the transcription factor, SIX5, using a new panel of monoclonal antibodies. Pham, Y.C., Man, N., Holt, I., Sewry, C.A., Pall, G., Johnson, K., Morris, G.E. J. Cell. Biochem. (2005) [Pubmed]
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