Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1

来自 EBSCO

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作者：

RA Saleem，BB Sharmila，FB Berry，AD Baxevanis，MA Walter

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摘要：

Five missense mutations (P79L, P79T, I91S, I91T and R127H) within the forkhead DNA-domain of the transcription factor, identified in patients with Axenfeld-Rieger (AR) malformations, were studied to identify the effects of these mutations on structure and function. Molecular modeling and threading analyses predict that the I91S and T mutations may generate local disruptions to the structure of the forkhead domain while the R127H mutation alters the electrostatic charge of the DNA surface of the forkhead domain. The P79L and T mutations are not predicted to grossly perturb the structure of the forkhead domain. Biological analyses indicate that all of these missense mutations cause a range of perturbations, including nuclear , reduced or abolished DNA capacity, and a reduction in the transactivation capacity of . These experiments extend our previous hypothesis that reduced transactivation of appropriate target genes by , underlie AR malformations mapping to 6p25. Importantly, these results can also be applied to predict the consequences of the molecular effects of mutations of other FOX genes that have analogous missense mutations, including , and .

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关键词：

aflatoxin-B1 aflatoxin-M1 spin trapping hydroxyl radicals lipid radicals desferoxamine mesylate SKF525A gadolinium chloride HPLC-ESR free radicals