Petrizzelli Francesco, Biagini Tommaso, Barbieri Alessandro, Parca Luca, Panzironi Noemi, Castellana Stefano, Caputo Viviana, Vescovi Angelo Luigi, Carella Massimo, Mazza Tommaso
Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy.
Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Comput Struct Biotechnol J. 2020 Jul 25;18:2033-2042. doi: 10.1016/j.csbj.2020.07.013. eCollection 2020.
Mutations in genes encoding for histone methylation proteins are associated with several developmental disorders. Among them, is the disease causative gene of type 2 Kabuki Syndrome, a rare multisystem disease. While nonsense mutations and short insertions/deletions are known to trigger pathogenic mechanisms, the functional effects of missense mutations are still uncharacterized. In this study, we demonstrate that a selected set of missense mutations significantly hamper the interaction between KDM6A and the histone H3, by modifying the dynamics of the linker domain, and then causing a loss of function effect.
编码组蛋白甲基化蛋白的基因突变与多种发育障碍有关。其中，KMT2D是2型歌舞伎综合征的致病基因，这是一种罕见的多系统疾病。虽然已知无义突变和短插入/缺失会触发致病机制，但错义突变的功能影响仍未明确。在本研究中，我们证明一组选定的错义突变通过改变连接域的动力学，显著阻碍了KDM6A与组蛋白H3之间的相互作用，进而导致功能丧失效应。
