Search results for "Histone-Lysine N-Methyltransferase"
showing 10 items of 29 documents
Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.
2018
International audience; Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 fami…
Broad neurodevelopmental features and cortical anomalies associated with a novel de novo KMT2A variant in Wiedemann-Steiner syndrome.
2021
Abstract Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder including developmental delay/intellectual disability (DD/ID), hypertrichosis cubiti, short stature, and distinctive facial features, caused by mutation in KMT2A gene, which encodes a histone methyltransferase (H3K4) that regulates chromatin-mediated transcription. Different neurodevelopmental phenotypes have been described within the WDSTS spectrum, including a peculiar Autism Spectrum Disorder (ASDs) subtype in some affected individuals. Here, we report a 9-year-old Caucasian male found by next-generation panel sequencing to carry a novel heterozygous de novo KMT2A frameshift variant (NM_001197104.2:c.4433delG; p. Arg1…
Genomic profiling in advanced stage non-small-cell lung cancer patients with platinum-based chemotherapy identifies germline variants with prognostic…
2017
Abstract Objective The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment. Materials and Methods We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain). Results We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 al…
DICER- and MMSET-catalyzed H4K20me2 recruits the nucleotide excision repair factor XPA to DNA damage sites
2017
The endoribonuclease DICER facilitates chromatin decondensation during lesion recognition following UV exposure. Chitale and Richly show that DICER mediates the recruitment of the methyltransferase MMSET, which catalyzes the dimethylation of histone H4 at lysine 20 and facilitates the recruitment of the nucleotide excision repair factor XPA.
E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases
2018
RAS proteins are major human oncogenes, and most of the studies are focused on enzymatic RAS effectors. Recently, nonenzymatic RAS effectors (RASSF, RAS association domain family) have garnered special attention because of their tumor-suppressive properties in contrast to the oncogenic potential of the classical enzymatic RAS effectors. Whereas most members of RASSF family are deregulated by promoter hypermethylation, RASSF8 promoter remains unmethylated in many cancers but the mechanism(s) of its down-regulation remains unknown. Here, we unveil E4BP4 as a critical transcriptional modulator repressing RASSF8 expression through histone methyltransferases, G9a and SUV39H1. In line with these …
Structural and mechanistic insights into the interaction of the circadian transcription factor BMAL1 with the KIX domain of the CREB-binding protein
2019
JBC papers in press xx, 16604-16619 (2019). doi:10.1074/jbc.RA119.009845
Customised next-generation sequencing multigene panel to screen a large cohort of individuals with chromatin-related disorder
2020
BackgroundThe regulation of the chromatin state by epigenetic mechanisms plays a central role in gene expression, cell function, and maintenance of cell identity. Hereditary disorders of chromatin regulation are a group of conditions caused by abnormalities of the various components of the epigenetic machinery, namely writers, erasers, readers, and chromatin remodelers. Although neurological dysfunction is almost ubiquitous in these disorders, the constellation of additional features characterizing many of these genes and the emerging clinical overlap among them indicate the existence of a community of syndromes. The introduction of high-throughput next generation sequencing (NGS) methods f…
Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes
2020
Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as “writer” of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann–Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein–Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generati…
Familial Sotos syndrome caused by a novel missense mutation, C2175S, in NSD1 and associated with normal intelligence, insulin dependent diabetes, bro…
2009
We report a familial Sotos syndrome in two children, boy and girl, aged 17 and 8 years, and in their 44 year old mother, who displayed normal intelligence at adult age, but suffered from insulin dependent diabetes mellitus, bronchial asthma, and severe lipedema. The underlying missense mutation, C2175S, occurred in a conserved segment of the NSD1 gene. Our findings confirm that familial cases of SS are more likely to carry missense mutations. This case report may prove useful to avoid underestimation of the recurrence rate of SS, and to demonstrate that the developmental delay may normalize, enabling an independent life and having an own family.
Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells
2010
MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP- or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34+ cells. These chromatin-modifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential fo…