ArticleProceedings of the National Academy of Sciences of the United States of America2010
Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability and lead to cross-beta aggregates.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46 citing papers in PubMed, 88 citations in OpenAlex.
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- In-Frame Deletion of Dystrophin Exons 8-50 Results in DMD Phenotype.International journal of molecular sciences · 2023Article
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- Fiber optic Raman spectroscopy for the evaluation of disease state in Duchenne muscular dystrophy: An assessment using the mdx model and human muscle.Muscle & nerve · 2022Article
- In silico analysis of a novel pathogenic variant c.7G > A in C14orf39 gene identified by WES in a Pakistani family with azoospermia.Molecular genetics and genomics : MGG · 2022Article
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- Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability.Scientific reports · 2021Article
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- Influence of genetic variants in asparaginase pathway on the susceptibility to asparaginase-related toxicity and patients' outcome in childhood acute lymphoblastic leukemia.Cancer chemotherapy and pharmacology · 2021Article
- Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin-deficient mdx mice.International journal of experimental pathology · 2021Article
- CARD8 polymorphism rs2043211 protects against noise-induced hearing loss by causing the dysfunction of CARD8 protein.Environmental science and pollution research international · 2021Article
- Morpholino Oligomer-Induced Dystrophin Isoforms to Map the Functional Domains in the Dystrophin Protein.Molecular therapy. Nucleic acids · 2020Article
- Effects of Mini-Dystrophin on Dystrophin-Deficient, Human Skeletal Muscle-Derived Cells.International journal of molecular sciences · 2020Article
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Authors and funding
4 authors at 1 institution in 2 countries.
Funding
Abstract
A deficiency of functional dystrophin protein in muscle cells causes muscular dystrophy (MD). More than 50% of missense mutations that trigger the disease occur in the N-terminal actin binding domain (N-ABD or ABD1). We examined the effect of four disease-causing mutations--L54R, A168D, A171P, and Y231N--on the structural and biophysical properties of isolated N-ABD. Our results indicate that N-ABD is a monomeric, well-folded alpha-helical protein in solution, as is evident from its alpha-helical circular dichroism spectrum, blue shift of the native state tryptophan fluorescence, well-dispersed amide crosspeaks in 2D NMR (15)N-(1)H HSQC fingerprint region, and rotational correlation time calculated from NMR longitudinal (T(1)) and transverse (T(2)) relaxation experiments. Compared to WT, three mutants--L54R, A168D, and A171P--show a decreased alpha-helicity and do not show a cooperative sigmoidal melt with temperature, indicating that these mutations exist in a wide range of conformations or in a "molten globule" state. In contrast, Y231N has an alpha-helical content similar to WT and shows a cooperative sigmoidal temperature melt but with a decreased stability. All four mutants experience serious misfolding and aggregation. FT-IR, circular dichroism, increase in thioflavin T fluorescence, and the congo red spectral shift and birefringence show that these aggregates contain intermolecular cross-beta structure similar to that found in amyloid diseases. These results indicate that disease-causing mutants affect N-ABD structure by decreasing its thermodynamic stability and increasing its misfolding, thereby decreasing the net functional dystrophin concentration.
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