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Hobia Gole, Raymond Chuk, David Coman
Kabuki syndrome is a clinically and genetically heterogeneous congenital malformation syndrome with protean clinical manifestations. This reflects the important epigenetic role in embryonic development of the two genes currently known to be associated with Kabuki syndrome i.e., KMT2D and KDM6A, which are responsible for Kabuki syndrome 1 and Kabuki syndrome 2, respectively. Hypoglycemia is thought to be a rare manifestation of Kabuki syndrome; however it may be under diagnosed. Herein we describe the case of a 5-year-old girl with Kabuki syndrome 2 in whom persistent hyperinsulinism was diagnosed at 4 years of age...
August 8, 2016: Clinics and Practice
Yoichi Munehira, Ze Yang, Or Gozani
Histone methylation dynamics plays a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic and functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here, we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system...
October 11, 2016: Journal of Molecular Biology
M Phan, F Conte, K D Khandelwal, C W Ockeloen, T Bartzela, T Kleefstra, H van Bokhoven, M Rubini, H Zhou, C E L Carels
Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia...
December 2016: Human Genetics
Jordan Kardos, Shengjie Chai, Lisle E Mose, Sara R Selitsky, Bhavani Krishnan, Ryoichi Saito, Michael D Iglesia, Matthew I Milowsky, Joel S Parker, William Y Kim, Benjamin G Vincent
We report the discovery of a claudin-low molecular subtype of high-grade bladder cancer that shares characteristics with the homonymous subtype of breast cancer. Claudin-low bladder tumors were enriched for multiple genetic features including increased rates of RB1, EP300, and NCOR1 mutations; increased frequency of EGFR amplification; decreased rates of FGFR3, ELF3, and KDM6A mutations; and decreased frequency of PPARG amplification. While claudin-low tumors showed the highest expression of immune gene signatures, they also demonstrated gene expression patterns consistent with those observed in active immunosuppression...
March 17, 2016: JCI Insight
Christian Trolle, Morten Muhlig Nielsen, Anne Skakkebæk, Philippe Lamy, Søren Vang, Jakob Hedegaard, Iver Nordentoft, Torben Falck Ørntoft, Jakob Skou Pedersen, Claus Højbjerg Gravholt
Adults with 45,X monosomy (Turner syndrome) reflect a surviving minority since more than 99% of fetuses with 45,X monosomy die in utero. In adulthood 45,X monosomy is associated with increased morbidity and mortality, although strikingly heterogeneous with some individuals left untouched while others suffer from cardiovascular disease, autoimmune disease and infertility. The present study investigates the leukocyte DNAmethylation profile by using the 450K-Illumina Infinium assay and the leukocyte RNA-expression profile in 45,X monosomy compared with karyotypically normal female and male controls...
September 30, 2016: Scientific Reports
Jean-François Spinella, Pauline Cassart, Chantal Richer, Virginie Saillour, Manon Ouimet, Sylvie Langlois, Pascal St-Onge, Thomas Sontag, Jasmine Healy, Mark D Minden, Daniel Sinnett
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with variable prognosis. It represents 15% of diagnosed pediatric ALL cases and has a threefold higher incidence among males. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Using an integrative approach combining genomic and transcriptomic data, we molecularly characterized 30 pediatric T-ALLs and identified common recurrent T-ALL targets such as FBXW7, JAK1, JAK3, PHF6, KDM6A and NOTCH1 as well as novel candidate T-ALL driver mutations including the p...
September 1, 2016: Oncotarget
Ashleigh Long, Elena S Sinkovskaya, Andrew C Edmondson, Elaine Zackai, Samantha A Schrier Vergano
Kabuki syndrome (MIM 147920) is a well-described, multiple congenital anomaly syndrome characterized by growth and developmental delay, cardiac, renal, and vertebral anomalies, as well as persistent fetal finger pads and distinct facial features. Facies are characterized by long palpebral fissures with eversion of lateral third of the lower eyelid, resembling the "Kabuki make-up" theatre genre after which the syndrome is named. Kabuki syndrome is estimated to affect 1/32,000 births, with 55-80% of patients showing nonsense or frameshift mutations in the KMT2D (MLL2) gene, which encodes a histone transferase located on chromosome 12q...
August 29, 2016: American Journal of Medical Genetics. Part A
Nina Bögershausen, Umut Altunoglu, Filippo Beleggia, Gökhan Yigit, Hülya Kayserili, Peter Nürnberg, Yun Li, Janine Altmüller, Bernd Wollnik
Kabuki syndrome (KS) is a rare developmental disorder characterized by multiple congenital malformations, postnatal growth retardation, intellectual disability, and recognizable facial features. It is mainly caused by mutations in either KMT2D or KDM6A. We describe a 14-year-old boy with KS presenting with an unusual combination of bilateral microphthalmia with orbital cystic venous lymphatic malformation and neonatal cholestasis with bile duct paucity, in addition to the typical clinical features of KS. We identified the novel KMT2D mutation c...
August 17, 2016: American Journal of Medical Genetics. Part A
Nicola Fusco, Felipe C Geyer, Maria R De Filippo, Luciano G Martelotto, Charlotte K Y Ng, Salvatore Piscuoglio, Elena Guerini-Rocco, Anne M Schultheis, Laetitia Fuhrmann, Lu Wang, Achim A Jungbluth, Kathleen A Burke, Raymond S Lim, Anne Vincent-Salomon, Masamichi Bamba, Suzuko Moritani, Sunil S Badve, Shu Ichihara, Ian O Ellis, Jorge S Reis-Filho, Britta Weigelt
Adenoid cystic carcinoma of the breast is a rare histological type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes...
August 5, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Aditya Dutta, Clémentine Le Magnen, Antonina Mitrofanova, Xuesong Ouyang, Andrea Califano, Cory Abate-Shen
The NKX3.1 homeobox gene plays essential roles in prostate differentiation and prostate cancer. We show that loss of function of Nkx3.1 in mouse prostate results in down-regulation of genes that are essential for prostate differentiation, as well as up-regulation of genes that are not normally expressed in prostate. Conversely, gain of function of Nkx3.1 in an otherwise fully differentiated nonprostatic mouse epithelium (seminal vesicle) is sufficient for respecification to prostate in renal grafts in vivo...
June 24, 2016: Science
Hirofumi Rokutan, Fumie Hosoda, Natsuko Hama, Hiromi Nakamura, Yasushi Totoki, Eisaku Furukawa, Erika Arakawa, Shoko Ohashi, Tomoko Urushidate, Hironori Satoh, Hiroko Shimizu, Keiko Igarashi, Shinichi Yachida, Hitoshi Katai, Hirokazu Taniguchi, Masashi Fukayama, Tatsuhiro Shibata
Mucinous gastric carcinoma (MGC) is a unique subtype of gastric cancer with a poor survival outcome. Comprehensive molecular profiles and putative therapeutic targets of MGC remain undetermined. We subjected 16 tumour-normal tissue pairs to whole-exome sequencing (WES) and an expanded set of 52 tumour-normal tissue pairs to subsequent targeted sequencing. The latter focused on 114 genes identified by WES. Twenty-two histologically differentiated MGCs (D-MGCs) and 46 undifferentiated MGCs (U-MGCs) were analysed...
October 2016: Journal of Pathology
Zhixiang Wang, Yuan Liu, Yong Xue, Haiyan Hu, Jieyu Ye, Xiaodong Li, Zhigang Lu, Fanyi Meng, Shuang Liang
Berberine, an isoquinoline plant alkaloid, exhibits a wide range of biochemical and pharmacological effects. However, the precise mechanism of these bioactivities remains poorly understood. In this study, we found significant similarity between berberine and two epigenetic modulators (CG-1521 and TSA). Reverse-docking using berberine as a ligand identified lysine-N-methyltransferase as a putative target of berberine. These findings suggested the potential role of berberine in epigenetic modulation. The results of PCR array analysis of epigenetic chromatin modification enzymes supported our hypothesis...
October 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Nina Bögershausen, Vincent Gatinois, Vera Riehmer, Hülya Kayserili, Jutta Becker, Michaela Thoenes, Pelin Özlem Simsek-Kiper, Mouna Barat-Houari, Nursel H Elcioglu, Dagmar Wieczorek, Sigrid Tinschert, Guillaume Sarrabay, Tim M Strom, Aurélie Fabre, Gareth Baynam, Elodie Sanchez, Gudrun Nürnberg, Umut Altunoglu, Yline Capri, Bertrand Isidor, Didier Lacombe, Carole Corsini, Valérie Cormier-Daire, Damien Sanlaville, Fabienne Giuliano, Kim-Hanh Le Quan Sang, Honorine Kayirangwa, Peter Nürnberg, Thomas Meitinger, Koray Boduroglu, Barbara Zoll, Stanislas Lyonnet, Andreas Tzschach, Alain Verloes, Nataliya Di Donato, Isabelle Touitou, Christian Netzer, Yun Li, David Geneviève, Gökhan Yigit, Bernd Wollnik
Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel...
September 2016: Human Mutation
Jihua Ran, Hui Li, Huiwu Li
Background. KDM6A (Lysine (K)-Specific Demethylase 6A) is the driver gene related to esophageal squamous cell carcinoma (ESCC). In order to provide more biological insights into KDM6A, in this paper, we treat PPI (protein-protein interaction) network derived from KDM6A as a conceptual framework and follow it to review its biological function. Method. We constructed a PPI network with Cytoscape software and performed clustering of network with Clust&See. Then, we evaluate the pathways, which are statistically involved in the network derived from KDM6A...
2016: TheScientificWorldJournal
M L Nickerson, N Witte, K M Im, S Turan, C Owens, K Misner, S X Tsang, Z Cai, S Wu, M Dean, J C Costello, D Theodorescu
The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes...
June 6, 2016: Oncogene
Takahiro Kodama, Justin Y Newberg, Michiko Kodama, Roberto Rangel, Kosuke Yoshihara, Jean C Tien, Pamela H Parsons, Hao Wu, Milton J Finegold, Neal G Copeland, Nancy A Jenkins
Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMT-TFs)...
June 14, 2016: Proceedings of the National Academy of Sciences of the United States of America
Charlotte Pawlyn, Martin Kaiser, Christoph Heuck, Lorenzo Melchor, Christopher Wardell, Alex Murison, Shweta Chavan, David C Johnson, Dil B Begum, Nasrin Dahir, Paula Proszek, David A Cairns, Eileen Boyle, John Jones, Gordon Cook, Mark T Drayson, Roger Owen, Walter M Gregory, Graham Jackson, Bart Barlogie, Faith E Davies, Brian A Walker, Gareth Morgan
PURPOSE: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike in other B cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been previously reported. We sought to address this using results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. EXPERIMENTAL DESIGN: Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences...
May 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Molly Gale, Joyce Sayegh, Jian Cao, Michael Norcia, Peter Gareiss, Denton Hoyer, Jane S Merkel, Qin Yan
Lysine demethylase 5A (KDM5A/RBP2/JARID1A) is a histone lysine demethylase that is overexpressed in several human cancers including lung, gastric, breast and liver cancers. It plays key roles in important cancer processes including tumorigenesis, metastasis, and drug tolerance, making it a potential cancer therapeutic target. Chemical tools to analyze KDM5A demethylase activity are extremely limited as available inhibitors are not specific for KDM5A. Here, we characterized KDM5A using a homogeneous luminescence-based assay and conducted a screen of about 9,000 small molecules for inhibitors...
May 21, 2016: Oncotarget
Kyung Hyun Yoo, Sumin Oh, Keunsoo Kang, Chaochen Wang, Gertraud W Robinson, Kai Ge, Lothar Hennighausen
Establishment of the mammary luminal cell lineage is controlled primarily by hormones and through specific transcription factors (TFs). Previous studies have linked histone methyltransferases to the differentiation of mammary epithelium, thus opening the possibility of biological significance of counteracting demethylases. We have now demonstrated an essential role for the H3K27me3 demethylase KDM6A in generating a balanced alveolar compartment. Deletion of Kdm6a in the mammary luminal cell lineage led to a paucity of luminal cells and an excessive expansion of basal cells, both in vivo and in vitro The inability to form structurally normal ducts and alveoli during pregnancy resulted in lactation failure...
August 15, 2016: Molecular and Cellular Biology
Ferga C Gleeson, Sarah E Kerr, Benjamin R Kipp, Jesse S Voss, Douglas M Minot, Zheng Jin Tu, Michael R Henry, Rondell P Graham, George Vasmatzis, John C Cheville, Konstantinos N Lazaridis, Michael J Levy
BACKGROUND & AIMS: Less than 10% of registered drug intervention trials for pancreatic ductal adenocarcinoma (PDAC) include a biomarker stratification strategy. The ability to identify distinct mutation subsets via endoscopic ultrasound fine needle aspiration (EUS FNA) molecular cytology could greatly aid clinical trial patient stratification and offer predictive markers. We identified chemotherapy treatment naïve ampullary adenocarcinoma and PDAC patients who underwent EUS FNA to assess multigene mutational frequency and diversity with a surgical resection concordance assessment, where available...
May 18, 2016: Oncotarget
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