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Fig. 7. Mutations in titin M10 that are associated with TMD and LGMD2J weaken the interaction with obscurin and Obsl1. (A) Y2H assay showed no reporter gene activity for either Finnish (Fin) or French (Fr) TMD M10 mutants. WT, wild type; Be, Belgian mutation; C, control. (B) The loss of binding was confirmed by GST pulldown assay. I, input; WT/Fin/Be/Fr, bound fraction on wild type M10 and on that containing the Finnish, Belgian and French mutation, respectively (see text for details). (C) Mutations in human M-band titin lead to disruptions in obscurin localization in diseased skeletal muscles. Obscurin localization (green) was compared with that of myomesin (red) in confocal analysis of cryosections of patient biopsies. In the presence of the Salih myopathy homozygous Mex3 deletion, general M-band morphology is disrupted, as shown by irregular myomesin striations. Even in areas with relatively normal-appearing myomesin stripes, obscurin is disrupted and localizes to split bands and longitudinal streaks, and diffusely. In skeletal muscles from LGMD2J patients, myomesin striations appear relatively normal, in agreement with the less-severe nature of the titin mutation. Obscurin is found in broad and diffuse stripes over the M-band, with loss of the tight colocalization with myomesin seen in normal control (ctrl) muscles. (Insets) Magnified 2x. Scale bars: 10 µm.
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