Mechanisms of pathogenesis of missense mutations on the KDM6A-H3 interaction in type 2 Kabuki Syndrome

Francesco Petrizzelli; Tommaso Biagini; Alessandro Barbieri; Luca Parca; Noemi Panzironi; Stefano Castellana; Viviana Caputo; Angelo Luigi Vescovi; Massimo Carella; Tommaso Mazza

doi:10.1016/j.csbj.2020.07.013

Mechanisms of pathogenesis of missense mutations on the KDM6A-H3 interaction in type 2 Kabuki Syndrome

Francesco Petrizzelli, Tommaso Biagini, Alessandro Barbieri, Luca Parca, Noemi Panzironi, Stefano Castellana, Viviana Caputo, Angelo Luigi Vescovi, Massimo Carella, Tommaso Mazza

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Mutations in genes encoding for histone methylation proteins are associated with several developmental disorders. Among them, KDM6A 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.

Original language	English (US)
Pages (from-to)	2033-2042
Number of pages	10
Journal	Computational and Structural Biotechnology Journal
Volume	18
DOIs	https://doi.org/10.1016/j.csbj.2020.07.013
State	Published - 2020

Keywords

Computational biology
Histone demethylation
KDM6A
Kabuki Syndrome
Molecular dynamics simulation

ASJC Scopus subject areas

Biotechnology
Biophysics
Structural Biology
Biochemistry
Genetics
Computer Science Applications

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10.1016/j.csbj.2020.07.013

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title = "Mechanisms of pathogenesis of missense mutations on the KDM6A-H3 interaction in type 2 Kabuki Syndrome",

abstract = "Mutations in genes encoding for histone methylation proteins are associated with several developmental disorders. Among them, KDM6A 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.",

keywords = "Computational biology, Histone demethylation, KDM6A, Kabuki Syndrome, Molecular dynamics simulation",

author = "Francesco Petrizzelli and Tommaso Biagini and Alessandro Barbieri and Luca Parca and Noemi Panzironi and Stefano Castellana and Viviana Caputo and Vescovi, {Angelo Luigi} and Massimo Carella and Tommaso Mazza",

note = "Funding Information: We gratefully acknowledge NVIDIA Corporation , the Amber Team and the “5x1000” voluntary contribution for supporting this research. Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

doi = "10.1016/j.csbj.2020.07.013",

language = "English (US)",

volume = "18",

pages = "2033--2042",

journal = "Computational and Structural Biotechnology Journal",

issn = "2001-0370",

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T1 - Mechanisms of pathogenesis of missense mutations on the KDM6A-H3 interaction in type 2 Kabuki Syndrome

AU - Petrizzelli, Francesco

AU - Biagini, Tommaso

AU - Barbieri, Alessandro

AU - Parca, Luca

AU - Panzironi, Noemi

AU - Castellana, Stefano

AU - Caputo, Viviana

AU - Vescovi, Angelo Luigi

AU - Carella, Massimo

AU - Mazza, Tommaso

PY - 2020

Y1 - 2020

N2 - Mutations in genes encoding for histone methylation proteins are associated with several developmental disorders. Among them, KDM6A 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.

AB - Mutations in genes encoding for histone methylation proteins are associated with several developmental disorders. Among them, KDM6A 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.

KW - Computational biology

KW - Histone demethylation

KW - KDM6A

KW - Kabuki Syndrome

KW - Molecular dynamics simulation

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JO - Computational and Structural Biotechnology Journal

JF - Computational and Structural Biotechnology Journal

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Mechanisms of pathogenesis of missense mutations on the KDM6A-H3 interaction in type 2 Kabuki Syndrome

Abstract

Keywords

ASJC Scopus subject areas

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