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

• For further distinction of the molecular mechanisms underlying the cardiac phenotype of DM, in the present study, we characterized the cardiac conduction findings of mice with targeted disruption of Six5 gene [2].
• Six5 heterozygous mice (adult and young) and their age matched wild type littermates were studied using in vivo electrophysiologic techniques, echocardiography, heart rate variability and exercise tolerance testing [2].
• In mammals, Six5, Six4 and Six1 genes are co-expressed during mouse myogenesis [6].
• Promoter of mDMAHP/Six5: differential utilization of multiple transcription initiation sites and positive/negative regulatory elements [4].
• Myotonic dystrophy results from a trinucleotide repeat expansion between the myotonic dystrophy protein kinase gene (Dmpk), which encodes a serine-threonine protein kinase, and the Six5 gene, which encodes a homeodomain protein [7].

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].

References