Structural bioinformatics enhances the interpretation of somatic mutations in KDM6A found in human cancers. Comput Struct Biotechnol J 2022;20:2200-2211
Date
05/27/2022Pubmed ID
35615018Pubmed Central ID
PMC9111933DOI
10.1016/j.csbj.2022.04.028Scopus ID
2-s2.0-85130080827 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
The histone demethylase KDM6A has recently elicited significant attention because its mutations are associated with a rare congenital disorder (Kabuki syndrome) and various types of human cancers. However, distinguishing KDM6A mutations that are deleterious to the enzyme and their underlying mechanisms of dysfunction remain to be fully understood. Here, we report the results from a multi-tiered approach evaluating the impact of 197 KDM6A somatic mutations using information derived from combining conventional genomics data with computational biophysics. This comprehensive approach incorporates multiple scores derived from alterations in protein sequence, structure, and molecular dynamics. Using this method, we classify the KDM6A mutations into 136 damaging variants (69.0%), 32 tolerated variants (16.2%), and 29 variants of uncertain significance (VUS, 14.7%), which is a significant improvement from the previous classification based on the conventional tools (over 40% VUS). We further classify the damaging variants into 15 structural variants (SV), 88 dynamic variants (DV), and 33 structural and dynamic variants (SDV). Comparison with variant scoring methods used in current clinical diagnosis guidelines demonstrates that our approach provides a more comprehensive evaluation of damaging potential and reveals mechanisms of dysfunction. Thus, these results should be taken into consideration for clinical assessment of the damaging potential of each mutation, as they provide hypotheses for experimental validation and critical information for the development of mutant-specific drugs to fight diseases caused by KDM6A dysfunctions.
Author List
Chi YI, Stodola TJ, De Assuncao TM, Leverence EN, Smith BC, Volkman BF, Mathison AJ, Lomberk G, Zimmermann MT, Urrutia RAuthors
Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of WisconsinGwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Thiago Milech De Assuncao Research Scientist II in the Surgery department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
