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

Zeljka Korade-Mirnics, Jack Tarleton, Serenella Servidei, Renee R. Casey, Massimo Gennarelli, Elena Pegoraro, Corrado Angelini, Eric P. Hoffman

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3 Scopus citations


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 ~ 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.

Original languageEnglish (US)
Pages (from-to)1017-1023
Number of pages7
JournalHuman Molecular Genetics
Issue number6
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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