Effect of the myotonic dystrophy expanded (CTG){sub n} repeat on the transcripts of DMPK alleles
- and others
Myotonic dystrophy (DM) is a pleiotropic, autosomal dominantly inherited neuromuscular disease. The clinical phenotype is associated with an unstable (CTG){sub n} repeat in the 3{prime} untranslated region of the candidate gene, DM protein kinase (DMPK). The size of the unstable repeat generally increases through successive generations and correlates to a reasonable degree with the phenotype in a given family. In various studies both decreased and increased levels of mutant steady-state DMPK mRNA and protein levels have been observed and related to (CTG){sub n} repeat expansion. This has led to different proposals to explain the molecular disease mechanism (gene-dosage vs. gain-of-function effect). Using allele-specific transcript amplification, comparative and quantitative MIMIC RT-PCR, and mRNA stability assays for the exon 9-10 region of the DMPK gene, we report co-equal expression of mutant and normal alleles at both hnRNA and mRNA levels. Identical levels of overall mRNA and no allele-specific differences in mRNA stability were seen in adult-onset and congenital DM patients compared to normal controls. The expanded repeat did not appear to interfere with transcriptional initiation or increase or decrease the stability of either primary or mature transcript of the mutant and normal DMPK allele. Similar results were obtained for two homozygous DM sisters. Pairs of somatic cell hybrids - one of the pair containing the chromosome with the expanded (CTG){sub n} repeat, the other with the normal repeat - were generated. We observed equal hnRNA, but significantly reduced mRNA levels for DMPK from exon 8 to 15 for the hybrid containing the expanded repeat, suggesting aberrant processing of mutant hnRNA to mRNA. Therefore, the results of current studies on the effect of the expanded (CTG){sub n} repeat on post-transcriptional events such as splicing downstream of the exon 10 will be reported.
- OSTI ID:
- 134238
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0974
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
GENES
TRANSCRIPTION
GENE MUTATIONS
SPLICING
PATIENTS
HEREDITARY DISEASES
NERVOUS SYSTEM DISEASES
PHENOTYPE
MUSCLES
PROTEINS
SIZE
CORRELATIONS
PHOSPHOTRANSFERASES
MESSENGER-RNA
STABILITY
SOMATIC CELLS
HYBRIDIZATION
NUCLEOTIDES
DOMINANT MUTATIONS
POLYMERASE CHAIN REACTION
EXONS