Deletion of UTX, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32567 | GEO | 2012/01/01
SECONDARY ACCESSION(S): PRJNA147127
REPOSITORIES: GEO
Similar Datasets
Project description:Kabuki syndrome (KS) is a rare multiple congenital anomalies/mental retardation (MCA/MR) syndrome described in 19811,2. In 2010, exome sequencing identified MLL2 mutations in patients with KS3. Since then, 5 studies identified a mutation in MLL2 in 56-75,6% of KS patients3-7. Here, we describe 2 KS and 1 KS-like patient with a de novo partial or complete deletion of UTX, a histone demethylase interacting with MLL2 in gene regulation. UTX locates on the X chromosome and we showed that the X chromosome with the deleted copy of UTX is preferentially inactivated despite the fact that UTX escapes X-inactivation. This study unveiled deletion of UTX as a second cause of KS and highlights the growing role of histone methylase/demethylase in MCA/MR syndrome. Two patients were analysed by Agilent array CGH 244K (AMADID: 014693) Three patients DNA were analyzed by CGH on custom targeted array 44K (AMADID: 032482). Two of them were initially analyzed using 244K Whole genome Arrays (AMADID: 014693). One third patient was selected given suspicion of deletion in one of the targeted gene (KDM6A) as amplification of some exons performed in our lab to sequence this gene failed.
2012-01-01 | E-GEOD-32567 | biostudies-arrayexpress
Project description:The interplay between multiple transcription factors precisely regulates eukaryotic transcription. Here, we report that the protein methyltransferases, MLL2 and PRMT1, interact directly and act collectively to regulate gene expression. PRMT1 binds to the N-terminal region of MLL2, considered an intrinsically disordered region, and methylates multiple arginine residues within its RGG/RG motifs. Notably, overexpression of PRMT1 decreased poly-ubiquitylation of MLL2, whereas mutations on methylation sites in MLL2 increased MLL2 poly-ubiquitylation, suggesting that PRMT1-mediated methylation stabilizes MLL2. MLL2 and PRMT1 cooperatively stimulated the expression of a chromosomal reporter gene in a PRMT1-mediated, MLL2-methylation–dependent manner. RNA-seq analysis found that MLL2 and PRMT1 jointly regulate the expression of genes involved in cell membrane and extracellular matrix functions, and depletion of either resulted in impaired cell migration and invasion. Our study provides evidence that PRMT1-mediated MLL2 methylation regulates MLL2 protein stability and the expression of their target genes.
2024-10-21 | GSE274754 | GEO
Project description:Background Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. Methods Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n=4) versus controls (n=4). Findings Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation.
2024-06-05 | GSE261686 | GEO
Project description:The UTX/KDM6A gene encodes the UTX histone H3K27 demethylase, which plays an important role in mammalian development and is frequently mutated in cancers and particularly, in urothelial cancers. Using BioID technique, we explored the interactome of different UTX isoforms.
2024-01-28 | PXD041254 | Pride
Project description:Deletion of UTX, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.
| PRJNA147127 | ENA
Project description:Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n=4) versus controls (n=4). Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. Our data reveals that lysine methyltransferase epigenetic regulation is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders.
2024-06-23 | PXD050547 | Pride
Project description:Somatic mutations of the MLL2 methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), these mutations are highly recurrent and occur early during tumorigenesis, suggesting a central role in transformation. Here we show that FL/DLBCL-associated MLL2 mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in germinal center (GC) B cells and DLBCL, consistent with the enrichment of MLL2 binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Mll2 early during B cell development, but not after initiation of the GC reaction, leads to an increase in GC B cells, whose transcriptional profile is enriched in cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Mll2-deficient B cells exhibit proliferative advantage ex vivo. Loss of Mll2 combined with BCL2 deregulation, mimicking FL/DLBCL pathogenesis, leads to an increased incidence of clonal lymphoproliferations resembling the features of the human tumors. These findings suggest that early MLL2 loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of MLL2-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events. ChIP-seq analysis of MLL2 bound regions and histone methylation (H3K4me3, H3K4me1) in normal human germinal center B cells.
2015-09-10 | E-GEOD-67494 | biostudies-arrayexpress
Project description:We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (cases) and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome.
| S-EPMC2930028 | biostudies-literature
Project description:Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.
| S-EPMC3121928 | biostudies-literature
Project description:BackgroundKabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause.MethodsGenomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools.ResultsWe identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site.ConclusionsThis study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.
| S-EPMC3141365 | biostudies-literature