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Related Concept Videos

Satellite Stem Cells and Muscular Dystrophy01:21

Satellite Stem Cells and Muscular Dystrophy

Satellite stem cells or myosatellite cells are quiescent stem cells that Alexander Mauro first identified in 1961. These cells are located between the sarcolemma, the plasma membrane of muscle fibers, and the basal lamina, the connective tissue sheath covering it. These mononucleated cells are activated in response to muscle injury, can transform into myoblasts, and may form or repair muscle fibers. Myosatellite cells can provide additional myonuclei for muscle regeneration or return to a...
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Mutations01:35

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
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Amyloid Fibrils03:03

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Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
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Amyloid Fibrils03:03

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Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy
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Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability and lead to cross-beta

Surinder M Singh1, Narsimulu Kongari, Javier Cabello-Villegas

  • 1Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology, School of Pharmacy, Aurora, CO 80045, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 11, 2010
PubMed
Summary
This summary is machine-generated.

Disease-causing mutations in the N-terminal actin binding domain (N-ABD) of dystrophin lead to muscular dystrophy (MD). These mutations cause N-ABD misfolding and aggregation, reducing functional dystrophin levels.

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Published on: September 14, 2019

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Muscular dystrophy (MD) is caused by a deficiency in functional dystrophin protein.
  • Over 50% of missense mutations leading to MD occur in the N-terminal actin binding domain (N-ABD).

Purpose of the Study:

  • To investigate the structural and biophysical effects of four specific disease-causing mutations (L54R, A168D, A171P, Y231N) on isolated N-ABD.

Main Methods:

  • Circular dichroism spectroscopy to assess alpha-helicity and thermal stability.
  • Tryptophan fluorescence spectroscopy to monitor protein folding.
  • Nuclear Magnetic Resonance (NMR) spectroscopy (2D 15N-1H HSQC, T1/T2 relaxation) to analyze protein structure and dynamics.
  • Fourier Transform Infrared (FT-IR) spectroscopy, Thioflavin T fluorescence, and Congo Red binding assays to detect protein misfolding and aggregation.

Main Results:

  • Wild-type N-ABD is a well-folded, monomeric, alpha-helical protein.
  • Mutations L54R, A168D, and A171P significantly decrease alpha-helicity, leading to molten globule states.
  • Mutation Y231N reduces thermodynamic stability but maintains alpha-helical content.
  • All four mutants exhibit severe misfolding and aggregation, forming intermolecular cross-beta structures characteristic of amyloid.

Conclusions:

  • Disease-causing mutations destabilize N-ABD structure and promote misfolding and aggregation.
  • These structural defects in N-ABD contribute to reduced functional dystrophin concentration and muscular dystrophy pathogenesis.
  • Targeting N-ABD misfolding could be a therapeutic strategy for muscular dystrophy.