title: Myotonic dystrophy: tissue-specific effect of somatic CTG expansions on allele-specific DMAHP/SIX5 expression.
abstract: 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.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA,
authors.forename: Z
authors.initials: Z
authors.lastname: Korade-Mirnics
authors.forename: J
authors.initials: J
authors.lastname: Tarleton
authors.forename: S
authors.initials: S
authors.lastname: Servidei
authors.forename: R R
authors.initials: RR
authors.lastname: Casey
authors.forename: M
authors.initials: M
authors.lastname: Gennarelli
authors.forename: E
authors.initials: E
authors.lastname: Pegoraro
authors.forename: C
authors.initials: C
authors.lastname: Angelini
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000328:Adult; D000483:Alleles; D001344:Autopsy; D001706:Biopsy; D002648:Child; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; C106687:SIX5 protein, human