This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What is Myotonic Dystrophy?
Inheritance
The National Institutes of Health (NIH) currently recognizes more than 30 different types of muscular dystrophy, with myotonic dystrophy being the most common form that begins in adulthood [3]. Both types of myotonic dystrophy resemble an autosomal dominant inheritance patten, meaning that individuals only need one defective gene copy to be affected by the disease (Figure 2) [1]. Worldwide, myotonic dystrophy is still indeed rare, and it only affects 0.0125% of the population or 1 in 8000 people [2]. History Myotonic dystrophy was first discovered in 1909 by a German doctor named Hans Steinert in 1909 [4]. Up until the 1990s, the underlying genetic mechanisms of myotonic dystrophy were not well understood, and scientists and physicians classified myotonic dystrophy as a single disease with no type 1 or type 2 distinctions. In 1994, doctor Charles Thornton et al. published a paper detailing three patients present with a clinical form of myotonic dystrophy, but the CTG nucleotide repeats that are associated with the DM1 disease state were no where to be found after a Southern blot analysis on chromosome 19. This led Thornton et al. to conclude that a myotonic dystophy phenotype can present itself even without the DM1 associated CTG repeats [5]. In 2001, Liquori et al. confirmed that the phenotype observed by Thornton et al. was actually DM2 and that it was caused by a repeating CCTG nucleotide motif on chromosome 3 [6]. While excessive CCTG repeats seem to be the only genetic cause of DM2, the Muscular Dystrophy Association states that much less is known about the mechanisms underlying DM2, therefore justifying a need for future research efforts. |
CNBP Gene & Protein Function
Myotonic dystrophy type 2 (DM2) is caused by a mutation in the CNBP gene, which encodes the CCHC-type zinc-finger nucleic acid binding protein. The CNBP gene, also referred to as ZNF9 (zinc finger protein 9), is found near the center of the chromosome 3's long arm at the position 21.3 (Figure 3). The fully functional protein has seven zinc-finger domains, a common structural protein motif that utilizes zinc ions to stabilize specific protein folds that in turn can bind to specific DNA and RNA sequences [7,8]. The CNBP gene is expressed all throughout the human body, with the greatest expression found in muscular regions, specifically skeletal muscle regions and the heart [7].
To date, CNBP is the only known gene that causes DM2 when mutated. The first intron, or first non-protein encoding region of CNBP, contains a repeating (TG)n(TCTG)n(CCTG)n motif within the mRNA code [9]. The last portion of this motif is the CCTG sequence, and is usually repeated fewer than twenty-six times in healthy individuals [7]. The CCTG sequence is referred to in the scientific literature as a tetranucleotide repeat, and expansion of this specific tetranucleotide repeat beyond the normal range can lead to DM2. In affected individuals, the CCTG sequence repeats an average of 5,000 times [6], with a range of 75-11,000 repeats depending upon the individual [9]. The CNBP gene is a highly conserved gene across various muscular organisms, and more specifically, across mammals (see the 'Homology' page under the 'Protein' tab). While there is a vast amount of literature supporting the claim that excess CCTG repeats are responsible for DM2, the specific function of the CNBP gene remains unknown. Recent studies, such as Benhalevy et al. 2017 have suggested that CNBP has binding sites on various mRNAs in the cell and functions to help enhance translation of cellular proteins, some of which may be essential to muscle function [10]. |
Signs & Symptoms of Myotonic Dystrophy
Resources & Foundations
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References
- Myotonic dystrophy - Genetics Home Reference. (2010, November). Retrieved from https://ghr.nlm.nih.gov/condition/myotonic-dystrophy#
- Learning About Myotonic Dystrophy. (2018, July 5). Retrieved from https://www.genome.gov/25521207/learning-about-myotonic-dystrophy/
- Muscular Dystrophy: Hope Through Research. (2017, February 7). Retrieved from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Muscular-Dystrophy-Hope-Through-Research
- Steinberg, H., & Wagner, A. (2008). Hans Steinert: Zum 100. Jahrestag der Erstbeschreibung der myotonen Dystrophie. Der Nervenarzt, 79(8), 961-970. doi:10.1007/s00115-008-2502-6
- Thornton, C. A., Griggs, R. C., & Moxley, R. T. (1994). Myotonic dystrophy with no trinucleotide repeat expansion. Annals of Neurology, 35(3), 269-272. doi:10.1002/ana.410350305
- Liquori, C. L. (2001). Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of ZNF9. Science, 293(5531), 864-867. doi:10.1126/science.1062125
- CNBP gene - Genetics Home Reference. (2010, October). Retrieved from https://ghr.nlm.nih.gov/gene/CNBP#
- Laity, J. H., Lee, B. M., & Wright, P. E. (2001). Zinc finger proteins: new insights into structural and functional diversity. Current Opinion in Structural Biology, 11(1), 39-46. doi:10.1016/s0959-440x(00)00167-6
- Myotonic Dystrophy Type 2 [Review]. (2006). GeneReviews. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1466/
- Benhalevy, D., Gupta, S. K., Danan, C. H., Ghosal, S., Sun, H., Kazemier, H. G., . . . Juranek, S. A. (2017). The Human CCHC-type Zinc Finger Nucleic Acid-Binding Protein Binds G-Rich Elements in Target mRNA Coding Sequences and Promotes Translation. Cell Reports, 18(12), 2979-2990. doi:10.1016/j.celrep.2017.02.080
- Meola, G., & Cardani, R. (2015). Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism. Journal of Neuromuscular Diseases, 2(S2). doi:10.3233/jnd-150088
- Myotonic Dystrophy (DM). (2018, January 09). Retrieved from https://www.mda.org/disease/myotonic-dystrophy
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Paxton Paine
University of Wisconsin-Madison, B.S. Biochemistry
[email protected]
Last updated 5/13/2018
http://genetics564.weebly.com
University of Wisconsin-Madison, B.S. Biochemistry
[email protected]
Last updated 5/13/2018
http://genetics564.weebly.com