ArticleHuman mutation2014
The ZZ domain of dystrophin in DMD: making sense of missense mutations.
Article in Human mutation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 29 citations in OpenAlex.
- Decoding splicing complexity: integrated genomic analysis reveals two novel pathogenic variants in Chinese dystrophinopathy pedigrees.Genes & genomics · 2025Article
- Article
- Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies.Orphanet journal of rare diseases · 2024Article
- Dp71 Point Mutations Induce Protein Aggregation, Loss of Nuclear Lamina Integrity and Impaired Braf35 and Ibraf Function in Neuronal Cells.International journal of molecular sciences · 2022Article
- The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction.Communications biology · 2022Review
- The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin.Nature cell biology · 2020Article
- EMQN best practice guidelines for genetic testing in dystrophinopathies.European journal of human genetics : EJHG · 2020Article
- CUGC for Duchenne muscular dystrophy (DMD).European journal of human genetics : EJHG · 2018Article
- Beware the laboratory report: discrepancy in variant classification on reproductive carrier screening.Genetics in medicine : official journal of the American College of Medical Genetics · 2018Article
- Evaluation of point mutations in dystrophin gene in Iranian Duchenne and Becker muscular dystrophy patients: introducing three novel variants.Journal of genetics · 2016Article
- The importance of genetic diagnosis for Duchenne muscular dystrophy.Journal of medical genetics · 2016Review
- Article
- Article
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Authors and funding
14 authors at 5 institutions in 1 country.
Funding
Abstract
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.
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