The ZZ Domain of Dystrophin in DMD: Making Sense of Missense Mutations
| Autor: | Eric K. Johnson, James M. Ervasti, Dana M. Strandjord, Nicolas Wein, William C. Ray, Andrew R. Findlay, Kevin M. Flanigan, Michael T. Howard, Yuuki Kaminoh, Adeline Vulin, Laura E. Taylor, Tabatha R. Simmons, Federica Montanaro, Baijayanta Maiti |
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| Rok vydání: | 2013 |
| Předmět: |
musculoskeletal diseases
Protein Folding congenital hereditary and neonatal diseases and abnormalities Duchenne muscular dystrophy Mutation Missense Mice Transgenic medicine.disease_cause Article Dystrophin WW domain Mice Glycoprotein complex Utrophin Genetics medicine Animals Humans Missense mutation Cysteine Dystroglycans Genetics (clinical) Aspartic Acid Mutation biology Protein Stability Genetic Variation Zinc Fingers musculoskeletal system medicine.disease Actins Transmembrane protein Muscular Dystrophy Duchenne biology.protein |
| Zdroj: | Human Mutation. 35:257-264 |
| ISSN: | 1059-7794 |
| DOI: | 10.1002/humu.22479 |
| Popis: | Duchenne muscular dystrophy (DMD) is associated with the loss of dystrophin, which plays an important role in myofiber integrity via interactions with β-dystroglycan and other members of the transmembrane dystrophin-associated protein complex. The ZZ domain, a cysteine-rich zinc-finger domain near the dystrophin C-terminus, is implicated in forming a stable interaction between dystrophin and β-dystroglycan, but the mechanism of pathogenesis of ZZ missense mutations has remained unclear because not all such mutations have been shown to alter β-dystroglycan binding in previous experimental systems. We engineered three ZZ mutations (p.Cys3313Phe, p.Asp3335His, and p.Cys3340Tyr) into a short construct similar to the Dp71 dystrophin isoform for in vitro and in vivo studies and delineated their effect on protein expression, folding properties, and binding partners. Our results demonstrate two distinct pathogenic mechanisms for ZZ missense mutations. The cysteine mutations result in diminished or absent subsarcolemmal expression because of protein instability, likely due to misfolding. In contrast, the aspartic acid mutation disrupts binding with β-dystroglycan despite an almost normal expression at the membrane, confirming a role for the ZZ domain in β-dystroglycan binding but surprisingly demonstrating that such binding is not required for subsarcolemmal localization of dystrophin, even in the absence of actin binding domains. |
| Databáze: | OpenAIRE |
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