Deletion of KDM6A, a Histone Demethylase Interacting with MLL2, in Three Patients with Kabuki Syndrome

Abstract

Kabuki syndrome (KS) is a rare genetic disease that causes developmental delay and congenital anomalies. Since the identification of MLL2 mutations as the primary cause of KS, such mutations have been identified in 56%-76% of affected individuals, suggesting that there may be additional genes associated with KS. Here, we describe three KS individuals with de novo partial or complete deletions of an X chromosome gene, KDM6A, that encodes a histone demethylase that interacts with MLL2. Although KDM6A escapes X inactivation, we found a skewed X inactivation pattern, in which the deleted X chromosome was inactivated in the majority of the cells. This study identifies KDM6A mutations as another cause of KS and highlights the growing role of histone methylases and histone demethylases in multiple-congenital-anomaly and intellectual-disability syndromes.

CHARGEd with neural crest defects

“…CHD7 is a transcriptional cofactor of SOX2, regulating target genes like JAG1 (Alagille syndrome), Mycn (Feingold syndrome), and Gli3 (Pallister-Hall syndrome) phenotypes observed for CHARGE syndrome. The genes which are mutated in Kabuki syndrome are KMT2D, a histone H3 lysine 4 (H3K4) methyltransferase (Li et al, 2011;Ng et al, 2010), and KDM6A, a lysine-specific histone demethylase, that interacts with KMT2D (Lederer et al, 2012). KMT2D is required for setting the active mark, H3K4 di-and trimethylation, while KDM6A removes the repressive mark, H3K27 trimethylation.…”

Kabuki syndrome revisited

“…In light of recent findings, however, pre-existing data pertaining to the significance of the X chromosome in this etiology may indeed still be of great relevance. The recent identification of the MLL2 gene believed to be implicative in KS, 3 and the more recently proposed X chromosomal interactions with this gene in a small subset of patients 24 have shed light on this ambiguity, and revealed the search into more complexed genomic interactions as a plausible line for further investigation.…”

“…Lederer et al 24 most recently published findings on data from two female and one male patient with KS. De novo partial or complete deletions of an X chromosome gene, KDM6A (lysine (K)-specific demethylase 6A, also known as UTX) were identified in all three patients.…”

Descrição de uma forma autossômica dominante de síndrome de Kabuki por mutação no gene <i>MLL2</i>

“…6,8,10 Mais recentemente, um grupo de pesquisa belga descobriu o envolvimento do gene KDM6A num pequeno grupo sem mutação no MLL2. 11 Esse gene regula a atividade genética de MLL2 nos processos de controle epigenéticos e pode ser resposável por casos de SK mesmo na ausência de mutações no MLL2.…”