Abstract

Myotonic Dystrophy is associated with a variable length expansion of a trinucleotide (CTG) segment with in the 3' untranslated region of the DM-kinase gene. The mutant allele of the DM kinase gene produces poly(A)-plus RNA at a much lower level (20-25%) than that seen with the normal allele in the same biopsies. the CTG expansion found in the mutant allele could therefore affect either (a) the site of transcription termination and influence the expression and polyadenylation of the DM-kinase or neighboring genes or (b) nuclear processing of the primary transcript containing the CTG- repeats. either of these effects may occur only in muscle cells or be more generalized in some individuals, accounting for the variable phenotypes associated with the disease. In order to test these hypotheses we set up a model system in which the CTG- repeats are placed in a heterologous gene and have observed their direct effect on gene expression. We propose to follow up on these preliminary studies and extend them to understand the molecular pathophysiology of the disease and gain possible insight into diagnosis and therapeutics.
Aim 1 is to further test the hypothesis that the defects seen in DM kinase RNA metabolism are a direct result of the CTG-expansion and not due to some other genetic modifiers which have yet to be mapped in the patients.
Aim 2 is to test the hypothesis that the CTG-repeats cause transcription termination by measuring transcription beyond the repeats and the normal end point of the gene.
Aim 3 is to test the hypothesis that the CTG-repeats influence nuclear retention and/or mRNA stability.
Aim 4 is to test the hypothesis that the CTG-repeats inhibit polyadenylation. The results from these experiments should have implications for understanding expansion disorders and should provide information on normal muscle mRNA metabolism by identifying defect(s) in the process. the results may provide information enabling better prognostic diagnoses of patients and/or elucidate novel avenues for molecular therapeutics.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Comprehensive Center (P60)
Project #
5P60AR044811-02
Application #
6100674
Study Section
Project Start
1998-09-01
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Type
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Kao, Amy H; Lertratanakul, Apinya; Elliott, Jennifer R et al. (2013) Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus. Am J Cardiol 112:1025-32
Kao, Amy H; Wasko, Mary Chester M; Krishnaswami, Shanthi et al. (2008) C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis. Am J Cardiol 102:755-60
Sheu, Yah-Tyng; Zmuda, Joseph M; Cauley, Jane A et al. (2006) Nuclear receptor coactivator-3 alleles are associated with serum bioavailable testosterone, insulin-like growth factor-1, and vertebral bone mass in men. J Clin Endocrinol Metab 91:307-12
Faulkner, K A; Cauley, J A; Zmuda, J M et al. (2006) Higher 1,25-dihydroxyvitamin D3 concentrations associated with lower fall rates in older community-dwelling women. Osteoporos Int 17:1318-28
Cauley, Jane A; Lui, Li-Yung; Stone, Katie L et al. (2005) Longitudinal study of changes in hip bone mineral density in Caucasian and African-American women. J Am Geriatr Soc 53:183-9
Cauley, Jane A; Lui, Li-Yung; Ensrud, Kristine E et al. (2005) Bone mineral density and the risk of incident nonspinal fractures in black and white women. JAMA 293:2102-8
Walsh, Sean; Zmuda, Joseph M; Cauley, Jane A et al. (2005) Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men. J Appl Physiol 98:132-7
Riechman, Steven E; Balasekaran, G; Roth, Stephen M et al. (2004) Association of interleukin-15 protein and interleukin-15 receptor genetic variation with resistance exercise training responses. J Appl Physiol 97:2214-9
Cauley, Jane A; Zmuda, Joseph M; Wisniewski, Stephen R et al. (2004) Bone mineral density and prevalent vertebral fractures in men and women. Osteoporos Int 15:32-7
Roth, Stephen M; Zmuda, Joseph M; Cauley, Jane A et al. (2004) Vitamin D receptor genotype is associated with fat-free mass and sarcopenia in elderly men. J Gerontol A Biol Sci Med Sci 59:10-5

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