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https://www.readbyqxmd.com/read/28933623/the-defining-dna-methylation-signature-of-kabuki-syndrome-enables-functional-assessment-of-genetic-variants-of-unknown-clinical-significance
#1
Erfan Aref-Eshghi, Laila C Schenkel, Hanxin Lin, Cindy Skinner, Peter Ainsworth, Guillaume Paré, David Rodenhiser, Charles Schwartz, Bekim Sadikovic
Kabuki syndrome (KS) is caused by mutations in KMT2D, which is a histone methyltransferase involved in methylation of H3K4, a histone marker associated with DNA methylation. Analysis of >450,000 CpGs in 24 KS patients with pathogenic mutations in KMT2D and 216 controls, identified several genomic regions, along with 1,504 CpG sites with significant DNA methylation changes including a number of Hox genes and the MYO1F gene. Using the most differentiating and significant probes and regions we developed a "methylation variant pathogenicity (MVP) score," which enables 100% sensitive and specific identification of individuals with KS, which was confirmed using multiple public and internal patient DNA methylation databases...
September 21, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28884922/congenital-heart-defects-in-molecularly-proven-kabuki-syndrome-patients
#2
Maria Cristina Digilio, Maria Gnazzo, Francesca Lepri, Maria Lisa Dentici, Elisa Pisaneschi, Anwar Baban, Chiara Passarelli, Rossella Capolino, Adriano Angioni, Antonio Novelli, Bruno Marino, Bruno Dallapiccola
The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%)...
September 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28805986/histiocytic-sarcoma-new-insights-into-fna-cytomorphology-and-molecular-characteristics
#3
Yin P Hung, Scott B Lovitch, Xiaohua Qian
BACKGROUND: Histiocytic sarcoma (HS) is a rare malignant neoplasm showing morphologic and immunophenotypic features of histiocytes. Molecular characteristics of HS and fine-needle aspiration (FNA) criteria for its diagnosis have not been established. METHODS: A case series of HS in 8 FNA samples from 6 patients was reviewed along with histopathologic and clinical data. Immunohistochemistry was performed on cell blocks (3 cases), core biopsies (5 cases), and surgical specimens (4 cases)...
August 2017: Cancer
https://www.readbyqxmd.com/read/28801451/adult-high-grade-b-cell-lymphoma-with-burkitt-lymphoma-signature-genomic-features-and-potential-therapeutic-targets
#4
Alyssa Bouska, Chengfeng Bi, Waseem Lone, Weiwei Zhang, Ambreen Kedwaii, Tayla Heavican, Cynthia M Lachel, Jiayu Yu, Roberto Ferro, Nanees Eldorghamy, Timothy C Greiner, Julie Vose, Dennis D Weisenburger, Randy D Gascoyne, Andreas Rosenwald, German Ott, Elias Campo, Lisa M Rimsza, Elaine S Jaffe, Rita M Braziel, Reiner Siebert, Rodney R Miles, Sandeep Dave, Anupama Reddy, Jan Delabie, Louis M Staudt, Joo Y Song, Timothy W McKeithan, Kai Fu, Michael Green, Wing C Chan, Javeed Iqbal
The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene-signature (adult-mBL), revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24 and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes...
August 11, 2017: Blood
https://www.readbyqxmd.com/read/28793284/growth-hormone-therapy-in-children-with-kabuki-syndrome-1-year-treatment-results
#5
Dina A Schott, Willem J M Gerver, Constance T R M Stumpel
BACKGROUND/AIMS: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. METHODS: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year...
August 9, 2017: Hormone Research in Pædiatrics
https://www.readbyqxmd.com/read/28778067/exome-sequencing-analysis-of-murine-medulloblastoma-models-identifies-wdr11-as-a-potential-tumor-suppressor-in-group-3-tumors
#6
Lei Wei, Brian L Murphy, Gang Wu, Matthew Parker, John Easton, Richard J Gilbertson, Jinghui Zhang, Martine F Roussel
Mouse models of human cancers are widely used in cancer research, yet questions frequently arise regarding their faithfulness in recapitulating their human counterparts. To compare the somatic mutations of murine models with human medulloblastoma (MB), we performed whole-exome sequencing on 12 tumors representing three distinct medulloblastoma subgroups: Wnt, Sonic Hedgehog (Shh) and Group 3 (G3). In total, 64 somatic mutations were identified and validated, including 40 predicted to cause amino acid changes...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28669924/histone-h3-lysine-4-methyltransferase-kmt2d
#7
REVIEW
Eugene Froimchuk, Younghoon Jang, Kai Ge
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein over 5500 amino acids in size and is partially functionally redundant with KMT2C. KMT2D is widely expressed in adult tissues and is essential for early embryonic development. The C-terminal SET domain is responsible for its H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells...
September 5, 2017: Gene
https://www.readbyqxmd.com/read/28653505/development-of-kras-mutant-lung-adenocarcinoma-in-mice-with-knockout-of-the-airway-lineage-specific-gene-gprc5a
#8
Junya Fujimoto, Sayuri Nunomura-Nakamura, Yihua Liu, Wenhua Lang, Tina McDowell, Yasminka Jakubek, Dalia Ezzeddine, Joshua Kapere Ochieng, Jason Petersen, Gareth Davies, Junya Fukuoka, Ignacio I Wistuba, Erik Ehli, Jerry Fowler, Paul Scheet, Humam Kadara
Despite the urgency for prevention and treatment of lung adenocarcinoma (LUAD), we still do not know drivers in pathogenesis of the disease. Earlier work revealed that mice with knockout of the G-protein coupled receptor Gprc5a develop late onset lung tumors including LUADs. Here, we sought to further probe the impact of Gprc5a expression on LUAD pathogenesis. We first surveyed GPRC5A expression in human tissues and found that GPRC5A was markedly elevated in human normal lung relative to other normal tissues and was consistently downregulated in LUADs...
October 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28611940/involvement-of-chromatin-remodeling-genes-and-the-rho-gtpases-rhob-and-cdc42-in-ovarian-clear-cell-carcinoma
#9
Nicolai Skovbjerg Arildsen, Jenny-Maria Jönsson, Katarina Bartuma, Anna Ebbesson, Sofia Westbom-Fremer, Anna Måsbäck, Susanne Malander, Mef Nilbert, Ingrid A Hedenfalk
OBJECTIVE: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30-50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28608921/whole-exome-sequencing-reveals-critical-genes-underlying-metastasis-in-oesophageal-squamous-cell-carcinoma
#10
Wei Dai, Josephine Mun Yee Ko, Sheyne Sta Ana Choi, Zhouyou Yu, Luwen Ning, Hong Zheng, Vinod Gopalan, Kin Tak Chan, Nikki Pui-Yue Lee, Kwok Wah Chan, Simon Ying-Kit Law, Alfred King-Yin Lam, Maria Li Lung
Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, owing to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole-exome sequencing was performed for 41 primary tumours and 15 lymph nodes (LNs) with metastatic ESCCs. Eleven cases included matched primary tumours, synchronous LN metastases, and non-neoplastic mucosa. Approximately 50-76% of the mutations identified in primary tumours appeared in the synchronous LN metastases...
August 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28601352/comprehensive-genomic-characterization-of-upper-tract-urothelial-carcinoma
#11
Tyler J Moss, Yuan Qi, Liu Xi, Bo Peng, Tae-Beom Kim, Nader E Ezzedine, Maribel E Mosqueda, Charles C Guo, Bogdan A Czerniak, Michael Ittmann, David A Wheeler, Seth P Lerner, Surena F Matin
BACKGROUND: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. OBJECTIVE: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. DESIGN, SETTING, AND PARTICIPANTS: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis...
June 7, 2017: European Urology
https://www.readbyqxmd.com/read/28590022/on-the-significance-of-craniosynostosis-in-a-case-of-kabuki-syndrome-with-a-concomitant-kmt2d-mutation-and-3-2%C3%A2-mbp-de-novo-10q22-3q23-1-deletion
#12
Alexandra Topa, Lena Samuelsson, Lovisa Lovmar, Göran Stenman, Lars Kölby
Craniosynostosis has rarely been described in patients with Kabuki syndrome. We report here a boy with facial asymmetry due to combined premature synostosis of the right coronal and sagittal sutures as well as several symptoms reminiscent of Kabuki syndrome (KS). Our case supports previous observations and suggests that craniosynostosis is a part of the KS phenotype. The uniqueness of our case is the sporadic co-occurrence of two genetic disorders, that is, a de novo frameshift variant in the KMT2D gene and a de novo 3...
June 7, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28582546/the-contribution-of-homology-arms-to-nuclease-assisted-genome-engineering
#13
Oliver Baker, Sarah Tsurkan, Jun Fu, Barbara Klink, Andreas Rump, Mandy Obst, Andrea Kranz, Evelin Schröck, Konstantinos Anastassiadis, A Francis Stewart
Designer nucleases like CRISPR/Cas9 enable fluent site-directed damage or small mutations in many genomes. Strategies for their use to achieve more complex tasks like regional exchanges for gene humanization or the establishment of conditional alleles are still emerging. To optimize Cas9-assisted targeting, we measured the relationship between targeting frequency and homology length in targeting constructs using a hypoxanthine-guanine phosphoribosyl-transferase assay in mouse embryonic stem cells. Targeting frequency with supercoiled plasmids improved steeply up to 2 kb total homology and continued to increase with even longer homology arms, thereby implying that Cas9-assisted targeting efficiencies can be improved using homology arms of 1 kb or greater...
July 27, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28552796/epigenetic-modifications-in-poorly-differentiated-and-anaplastic-thyroid-cancer
#14
REVIEW
Thanyawat Sasanakietkul, Timothy D Murtha, Mahsa Javid, Reju Korah, Tobias Carling
Well-differentiated thyroid cancer accounts for the majority of endocrine malignancies and, in general, has an excellent prognosis. In contrast, the less common poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are two of the most aggressive human malignancies. Recently, there has been an increased focus on the epigenetic alterations underlying thyroid carcinogenesis, including those that drive PDTC and ATC. Dysregulated epigenetic candidates identified include the Aurora group, KMT2D, PTEN, RASSF1A, multiple non-coding RNAs (ncRNA), and the SWI/SNF chromatin-remodeling complex...
May 25, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28506208/a-strategy-to-apply-quantitative-epistasis-analysis-on-developmental-traits
#15
Marta K Labocha, Wang Yuan, Boanerges Aleman-Meza, Weiwei Zhong
BACKGROUND: Genetic interactions are keys to understand complex traits and evolution. Epistasis analysis is an effective method to map genetic interactions. Large-scale quantitative epistasis analysis has been well established for single cells. However, there is a substantial lack of such studies in multicellular organisms and their complex phenotypes such as development. Here we present a method to extend quantitative epistasis analysis to developmental traits. METHODS: In the nematode Caenorhabditis elegans, we applied RNA interference on mutants to inactivate two genes, used an imaging system to quantitatively measure phenotypes, and developed a set of statistical methods to extract genetic interactions from phenotypic measurement...
May 15, 2017: BMC Genetics
https://www.readbyqxmd.com/read/28486103/tackling-resistance-to-pi3k-inhibition-by-targeting-the-epigenome
#16
COMMENT
Shany Koren, Mohamed Bentires-Alj
Phosphoinositide-3-kinase (PI3K) pathway inhibitors have emerged as promising therapeutic agents for estrogen receptor (ERα)-positive breast cancers. However, incipient resistance limits the clinical benefit. Toska and colleagues identified that the epigenetic regulator KMT2D enhances ERα activity in BYL719-treated PIK3CA mutant breast cancer, leading to a rationale for targeting the epigenome and PI3K signaling.
May 8, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28483418/mll3-and-mll4-facilitate-enhancer-rna-synthesis-and-transcription-from-promoters-independently-of-h3k4-monomethylation
#17
Kristel M Dorighi, Tomek Swigut, Telmo Henriques, Natarajan V Bhanu, Benjamin S Scruggs, Nataliya Nady, Christopher D Still, Benjamin A Garcia, Karen Adelman, Joanna Wysocka
Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475860/charge-and-kabuki-syndromes-gene-specific-dna-methylation-signatures-identify-epigenetic-mechanisms-linking-these-clinically-overlapping-conditions
#18
Darci T Butcher, Cheryl Cytrynbaum, Andrei L Turinsky, Michelle T Siu, Michal Inbar-Feigenberg, Roberto Mendoza-Londono, David Chitayat, Susan Walker, Jerry Machado, Oana Caluseriu, Lucie Dupuis, Daria Grafodatskaya, William Reardon, Brigitte Gilbert-Dussardier, Alain Verloes, Frederic Bilan, Jeff M Milunsky, Raveen Basran, Blake Papsin, Tracy L Stockley, Stephen W Scherer, Sanaa Choufani, Michael Brudno, Rosanna Weksberg
Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7(LOF)) and lysine (K) methyltransferase 2D (KMT2D(LOF)), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder...
May 4, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28471124/multiplex-genomic-test-of-mutation-and-fusion-genes-in-small-biopsy-specimen-of-lung-cancer
#19
Fumihiro Oshita, Rika Kasajima, Yohei Miyagi
We evaluated multiple oncogenic mutations and fusion genes in small specimen obtained by bronchoscopy. Eight patients with lung cancer were recruited, 3 small cell lung cancer, 3 non-small cell lung cancer, 1 adenocarcinoma and 1 squamous cell carcinoma. A median value of extracted RNA and DNA amounts from specimen was 1573 ng (range 367.5 to 8900) and 6700 ng (range 550 to 68000 ng), respectively. We applied amplicon sequencing panels that cover exon regions of 41 genes related to lung tumorigenesis as well as total 61 major variants of ALK, ROS, RET or NTRK1 fusion transcripts...
July 2016: Journal of Experimental Therapeutics & Oncology
https://www.readbyqxmd.com/read/28440294/next-generation-dna-sequencing-identifies-novel-gene-variants-and-pathways-involved-in-specific-language-impairment
#20
Xiaowei Sylvia Chen, Rose H Reader, Alexander Hoischen, Joris A Veltman, Nuala H Simpson, Clyde Francks, Dianne F Newbury, Simon E Fisher
A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology...
April 25, 2017: Scientific Reports
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