Our results contribute to increasing our knowledge and understanding of the complete biochemical mechanism and the molecular basis for the phenotypic outcome of HMBS mutants, which is important in the future investigation of treatments for AIP.
Thus, our working hypothesis is that altered biophysical properties of double mutant sarcomeric proteins could interact to either heighten or mitigate the functional cellular outcomes of either mutant allele when studied in isolation.
In order to have a better understanding of pathological outcomes of a mutant protein, its conformational changes with respect to its native protein have to be studied at molecular level.
Therefore, this finding suggests either that the mutant p53γ isoform has an intrinsic activity abrogating the poor prognosis associated with p53 mutation or that p53γ is just an inactive marker of better outcomes for mutant p53 breast cancer patients.
The strongest evidence comes from the outcome of expressing the mutant ATZ gene in transgenic animals.
To test this hypothesis, we used co-immunoprecipitation and reporter gene assays to examine the activating and repressing effects of MCPH1 on a set of its down-stream genes and then compared the functional outcomes of a series of mutant MCPH1 proteins that carry mutations at the human- and great-ape-specific sites.
Comparison of outcome in mutant vs wild type or p value for interaction between treatment arm on a comparative study and mutation status.
Examples are treatment with HDAC6 inhibitors in HSPB1 mutant mice, restoring axonal transport defects [ 16], and treatment with curcumin improving outcome of neuropathy in MPZ mutant mice [ 56].
Much progress has been made over the years in our understanding of RAS genes and the critical role they play in tumorigenesis, yet we have been unable to exploit this knowledge to significantly improve the outcome of cancers driven by mutant KRAS.
A similar trend towards improved outcome of patients with B2M-mutant tumours was observed when analysing tumour-related deaths, as no tumour-related deaths were observed in B2M-mutant colon cancer patients (data not shown); however, differences in OS were not statistically significant (log-rank test P=0.64).
