p63 activates transcription of IRF6, whereas p63 mutant proteins causing ectodermal dysplasias are unable to activate IRF6 transcription (41, 42).
On the other hand, intracellular stress is triggered in chondrocytes synthesising mutant proteins, causing alterations in the secretory pathway, disturbing normal cell metabolism and proliferation, and, in extreme cases, leading to cell death (Nundlall et al., 2010; Piróg-Garcia et al., 2007; Rajpar et al., 2009; Saito et al., 2009; Tsang et al., 2007).
Overexpression of the RHEB mutant proteins caused an increase in soma size, confirming that these mutations do not cause a loss of function (Fig. 3a, b, one-way ANOVA, p < 0.0001, F 3,260) = 50.35; control vector vs. RHEB-WT: p < 0.0001; control vector vs. RHEBp.P37L: p < 0.0001; control vector vs. RHEBp.S68P: p < 0.0001 by Tukey's multiple comparisons test).
An alternative hypothesis explored here is that multiple CM mutant proteins cause allele-specific combinatorial primary effects that uniquely alter sarcomeric function and are not necessarily linked directly to total mutant gene dosage.
We have shown that FTD-specific CHMP2B mutant proteins cause enlarged late endosomes and disrupt endosome lysosome fusion in cell culture models.
Because mutant proteins cause different problems in different brain regions, brain-region-specific factors must play a role in determining selective vulnerability.
Interestingly, the p53 mutant proteins caused enhanced Nox4 protein levels either in the absence or in the presence of TGF- β, indicating a TGF- β-independent positive regulation of Nox4, whereas WT-p53 retained its repressive effect on TGF- β-induced Nox4 protein.
The results show that both the overexpression of the CUE-deletion and the CUE-point mutant protein caused diminished growth (Figure 9C).
Expression of the mutant protein caused the formation of very large vesicles (with a diameter of about 3 5 μm) that localized at the cell periphery (Fig. 2e, arrows).
In summary, the N17 domain of huntingtin is a multifunctional localization signal that regulates the subcellular localization of huntingtin, is regulated by post-translational modification and contributes to the pathogenic mechanism by which the mutant protein causes disease.
However, because the mutations are in the terminal exon and are unlikely to result in nonsense-mediated decay of the mRNA, and because patients are comparable in severity to the Canadian-null patients, it is also possible that the mutant protein causes a dominant negative effect.
