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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 

Myotonic dystrophy: tissue-specific effect of somatic CTG expansions on allele-specific DMAHP/ SIX5 expression.

Myotonic dystrophy ( DM), the most common inherited muscle disorder, is caused by a CTG expansion in the 3"-untranslated region of a protein kinase gene ( DMPK ). The complex and variable phenotype is most likely caused by a complex molecular pathogenesis, including deficiency of the DMPK protein, a trans -dominant misregulation of RNA homeostasis and haploinsufficiency of a neighboring homeobox gene [ DM locus-associated homeodomain protein ( DMAHP )]. Here, we study the allele-specific transcriptional activity of the DMAHP/ SIX5 gene in DM patient tissues. Using a quantitative fluorescent RT-PCR assay, we tested allele-specific accumulation of DMAHP/ SIX5 transcripts in both total and poly(A)+pools. In muscle biopsies, we found that transcript reductions of DMAHP/ SIX5 alleles in cis with CTG expansions correlated with the extent of expansion. A patient with approximately 90 CTG repeats in muscle DNA (normal n < 37) showed a 20% reduction of allele-specific transcript levels, while four other DM patients with larger expansions showed 80% reductions. The effects of the CTG expansions on DMAHP transcription were tissue specific: autopsy tissues from a patient with 1500 repeats showed 80% reductions in muscle and liver; however, RNA from other tissues (lung, aorta, heart conduction tissue, cerebellum) showed 0-20% reductions. Our results suggest that the effect of the CTG repeat on the DMAHP/ SIX5 promoter is variable and tissue-specific. Our data are consistent with abnormalities of DMAHP/ SIX5 probably having a more prominent role in disease pathogenesis in muscle, liver and brain, but being less important in other tissues.[1]

References

  1. 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)
 
 
 
 
 
 
 
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