Abstract
BackgroundKabuki syndrome is a genetic disorder that affects several body systems and presents with variations in symptoms and severity. The syndrome is named for a common phenotype of faces resembling stage makeup used in a Japanese traditional theatrical art named kabuki. The most frequent cause of this syndrome is mutations in the H3K4 family of histone methyltransferases while a smaller percentage results from genetic alterations affecting the histone demethylase, KDM6A. Because of the rare presentation of the latter form of the disease, little is known about how missense changes in the KDM6A protein sequence impact protein function.ResultsIn this study, we use molecular mechanic and molecular dynamic simulations to enhance the annotation and mechanistic interpretation of the potential impact of eleven KDM6A missense variants found in Kabuki syndrome patients. These variants (N910S, D980V, S1025G, C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W, and R1351Q) are predicted to be pathogenic, likely pathogenic or of uncertain significance by sequence-based analysis. Here, we demonstrate, for the first time, that although Kabuki syndrome missense variants are found outside the functionally critical regions, they could affect overall function by significantly disrupting global and local conformation (C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W and R1351Q), chemical environment (C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W and R1351Q), and/or molecular dynamics of the catalytic domain (all variants). In addition, our approaches predict that many mutations, in particular C1153R, could allosterically disrupt the key enzymatic interactions of KDM6A.ConclusionsOur study demonstrates that the KDM6A Kabuki syndrome variants may impair histone demethylase function through various mechanisms that include altered protein integrity, local environment, molecular interactions and protein dynamics. Molecular dynamics simulations of the wild type and the variants are critical to gain a better understanding of molecular dysfunction. This type of comprehensive structure- and MD-based analyses should help develop improved impact scoring systems to interpret the damaging effects of variants in this protein and other related proteins as well as provide detailed mechanistic insight that is not currently predictable from sequence alone.
Highlights
Kabuki syndrome is a genetic disorder that affects several body systems and presents with variations in symptoms and severity
We report a more comprehensive analytical approach that uses a wider set of scores derived from molecular mechanic calculations and molecular dynamics (MD) simulations using the published 3D structure of the catalytic domain of Histone lysine(K)-specific demethylase 6A (KDM6A) [21]
KDM6A is made of 1401 amino acids, which separates a linker region that joins two distinctive modular domains; the tetratricopeptide repeat (TPR) domain at the N-terminus and the catalytic domain at the C-terminus (Fig. 1a)
Summary
Kabuki syndrome is a genetic disorder that affects several body systems and presents with variations in symptoms and severity. Because of the rare presentation of the latter form of the disease, little is known about how mis‐ sense changes in the KDM6A protein sequence impact protein function. The current study focuses on the analyses of Kabuki-associated histone lysine-specific demethylase 6A, KDM6A, a well-known epigenomic regulator that functions as an eraser of methylated histone marks. All pathogenic KDM6A variants, known to result in loss of function mutations, can disrupt cell, organ, and systems homeostasis, impacting human health. Pathogenic KDM6A variants are one cause of Kabuki syndrome, a rare multisystemic disorder which presents in approximately one in every 32,000 newborns [12,13,14] and causes developmental defects, disturbed growth, multiple congenital organ malformations, as well as hematological and immunological anomalies [15]. The well-documented genotype-tophenotype correlation for these variants justifies the purpose of these studies, namely extending this knowledge toward better understanding their mechanisms of dysfunction at the molecular level with atomic resolution
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