The ZZ domain of dystrophin in DMD: making sense of missense mutations.
Article Details
- CitationCopy to clipboard
Vulin A, Wein N, Strandjord DM, Johnson EK, Findlay AR, Maiti B, Howard MT, Kaminoh YJ, Taylor LE, Simmons TR, Ray WC, Montanaro F, Ervasti JM, Flanigan KM
The ZZ domain of dystrophin in DMD: making sense of missense mutations.
Hum Mutat. 2014 Feb;35(2):257-64. doi: 10.1002/humu.22479. Epub 2013 Dec 2.
- PubMed ID
- 24302611 [ View in PubMed]
- Abstract
Duchenne muscular dystrophy (DMD) is associated with the loss of dystrophin, which plays an important role in myofiber integrity via interactions with beta-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 beta-dystroglycan, but the mechanism of pathogenesis of ZZ missense mutations has remained unclear because not all such mutations have been shown to alter beta-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 beta-dystroglycan despite an almost normal expression at the membrane, confirming a role for the ZZ domain in beta-dystroglycan binding but surprisingly demonstrating that such binding is not required for subsarcolemmal localization of dystrophin, even in the absence of actin binding domains.