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Gene Review

Six5  -  sine oculis-related homeobox 5

Mus musculus

Synonyms: DM locus-associated homeodomain protein homolog, Dmahp, Homeobox protein SIX5, MDMAHP, Sine oculis homeobox homolog 5, ...
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Disease relevance of Six5

  • Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts [1].
  • Six5 loss may partly contribute to conduction abnormalities in myotonic dystrophy, particularly infraHisian conduction delay, one of the initial phenotypes of adult-onset cardiac conduction abnormalities in DM patients [2].
  • Loss of Six5 results in male sterility and a progressive decrease in testicular mass with age [3].
  • For analysis of the regulatory elements in the promoter region, we used P19 embryonal carcinoma cells which abundantly express mouse DMAHP / Six5 [4].

High impact information on Six5

  • To test the role of Six5 loss in DM, we have analysed a strain of mice in which Six5 was deleted [1].
  • To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse Six5 by replacing the first exon with a beta-galactosidase reporter [5].
  • We demonstrate a strict requirement of Six5 for both spermatogenic cell survival and spermiogenesis [3].
  • Leydig cell hyperproliferation and increased intra-testicular testosterone levels are observed in the Six5-/- mice [3].
  • Thus, decreased c-Kit levels could contribute to the elevated spermatogenic cell apoptosis and Leydig cell hyperproliferation in the Six5-/- mice [3].

Biological context of Six5


Anatomical context of Six5

  • Genes expressed in the somites, skeletal muscles, brain and meninges comprised the majority, suggesting the role of Six5 in the development and function of mesodermal tissues and brain [8].

Other interactions of Six5

  • Six4 and Six5 single knockout (KO) mice have no developmental defects, while Six1 KO mice die at birth and show multiple organ developmental defects [6].

Analytical, diagnostic and therapeutic context of Six5

  • By echocardiography, left ventricular (LV) end-diastolic dimension was enlarged in adult Six5 heterozygous mice, although neither fractioning shortening nor LV wall thickness showed significant differences [2].
  • By overexpressing a constitutively active Six5 (VP16-Six5wt) using adenovirus-mediated gene transfer in P19 cells and subsequent expression profiling using cDNA arrays, 21 genes, whose expression level increased by the treatment, were identified as potential target genes [8].
  • We analyzed the expression of mouse DMAHP / Six5 (the myotonic dystrophy-associated homeodomain protein gene) during embryogenesis and in various tissues by northern blotting [4].
  • RT-PCR analysis shows that this gene, which we have called DM locus-associated homeodomain protein (DMAHP), is expressed in a number of human tissues, including skeletal muscle, heart and brain [9].


  1. Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. Sarkar, P.S., Appukuttan, B., Han, J., Ito, Y., Ai, C., Tsai, W., Chai, Y., Stout, J.T., Reddy, S. Nat. Genet. (2000) [Pubmed]
  2. Characterization of cardiac conduction system abnormalities in mice with targeted disruption of Six5 gene. Wakimoto, H., Maguire, C.T., Sherwood, M.C., Vargas, M.M., Sarkar, P.S., Han, J., Reddy, S., Berul, C.I. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing. (2002) [Pubmed]
  3. Six5 is required for spermatogenic cell survival and spermiogenesis. Sarkar, P.S., Paul, S., Han, J., Reddy, S. Hum. Mol. Genet. (2004) [Pubmed]
  4. Promoter of mDMAHP/Six5: differential utilization of multiple transcription initiation sites and positive/negative regulatory elements. Murakami, Y., Ohto, H., Ikeda, U., Shimada, K., Momoi, T., Kawakami, K. Hum. Mol. Genet. (1998) [Pubmed]
  5. 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]
  6. Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Grifone, R., Demignon, J., Houbron, C., Souil, E., Niro, C., Seller, M.J., Hamard, G., Maire, P. Development (2005) [Pubmed]
  7. Skeletal muscle Na currents in mice heterozygous for Six5 deficiency. Mistry, D.J., Moorman, J.R., Reddy, S., Mounsey, J.P. Physiol. Genomics (2001) [Pubmed]
  8. 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]
  9. A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat. Boucher, C.A., King, S.K., Carey, N., Krahe, R., Winchester, C.L., Rahman, S., Creavin, T., Meghji, P., Bailey, M.E., Chartier, F.L. Hum. Mol. Genet. (1995) [Pubmed]
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