Poster Session B
Genetics, genomics and proteomics
Ahmet Gul, MD
Division of Rheumatology, Department of Internal Medicine, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
Istanbul, Turkey
No financial relationships with ineligible companies to disclose
MD simulations of the WT and the mutants revealed that the cavity between two loops of SPRY; one from residue 672 to 680 and the other loop from residue 695 to 697, changed drastically in between mutants, and there was a clear drop in the cavity area of the most penetrant M694V mutation. The M694V mutation exhibited the most substantial negative MI profile shift, followed by the M680I, V726A, and the K695R mutations with a negligible negative shift; and positive shifts were ordered as K695R >M680I >V726A >M694V. The relatively less penetrant V726A was not located in the protein binding cavity, and this replacement resulted in allosteric changes leading to a decrease of MI along a path between A726 and M680, and an increase of the distance between A726 and S675. Deletion of M694, the most severe variant in the SPRY domain, led to extreme loss of MI.
Conclusion:
The current work demonstrated the utility of MI profile shifts in assessing the pathogenicity of mutations and the challenges in relating the shifts to disease severity in FMF. The importance of negative MI shifts as indicators of severe effects were emphasized, along with exploring potential compensatory mechanisms indicated by positive MI shifts, which were otherwise random and inconsequential. The current approach is expected to provide insights into the molecular mechanisms underlying disease pathogenesis as well.
Table 1. Predictions for the pathogenicity of Pyrin mutations by the SIFT, Polyphen-2, Provean, SAAMBE-3D, Mutabind2, mCSM-PPI2, and Varity softwares. The scores and predictions were calculated for both the whole Pyrin protein and the SPRY domain containing the residues between 586 and 781 as used in the MD analyses.
A. Hacisuleyman: None; A. Gul: None; B. Erman: None.