Structural investigation of tetranucleotide repeats implicated in myotonic dystrophy 2 (DM2)

Ghule, Komal Sanjeevan and Rathinavelan, Thenmalarchelvi (2018) Structural investigation of tetranucleotide repeats implicated in myotonic dystrophy 2 (DM2). Masters thesis, Indian Institute of Technology Hyderabad.

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Abstract

Myotonic dystrophy is an autosomal dominant, multisystemic disease characterized by progressive muscle wasting and weakness. Two distinct forms of the disease caused by similar mutations have been identified till now. Myotonic dystrophy type 1 (DM1, Steinert’s disease) is caused by a (CTG)n expansion in DMPK(dystrophia myotonica protein kinase) gene, while myotonic dystrophy type 2(DM2) is caused by a (CCTG)n expansion in CNBP(Cellular nucleic acid-binding protein) gene. These diseases combined together, affect 1 in 8000 individuals worldwide. RNA gain of function mechanism plays an important role in pathogenesis of disease. Therefore, it is essential to develop ligands that bind selectively to the pathogenic RNAs in preference to the natural targets and other nucleic acids. Molecular dynamic simulations are carried out to shed light on role of different mismatches on the CCUG structure. Structural investigation of CAGG antisense RNA in presence of different ions using circular dichroism is done which shows parallel G-quadruplex structure formation at high concentration of KCl. Interaction between various domains of MBNL1 protein and r(CCUG)5.r(CCUG)5 RNA duplex has also been explored.

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