Feedback Regulation of RTK Signaling in Development ⁎ Cynthia L
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Blueprint Genetics Hereditary Leukemia Panel
Hereditary Leukemia Panel Test code: ON0101 Is a 41 gene panel that includes assessment of non-coding variants. Is ideal for patients with a personal history of a syndrome that confers an increased risk of leukemia or patients with a family history of a syndrome that confers an increased risk of leukemia. About Hereditary Leukemia An inherited predisposition to hematological malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and bone marrow myelodysplastic syndrome (MDS) may be associated with syndromic features or occur as the principal clinical feature. MDSs and AMLs can occur in the context of syndromic bone marrow failure (eg. dyskeratosis congenita, Fanconi anemia). Other hereditary syndromes with an increased risk of leukemia include Li-Fraumeni syndrome (TP53), ataxia telangiectasia (ATM), Bloom syndrome (BLM), neurofibromatosis type 1 (NF1) and less frequently Noonan syndrome (PTPN11, CBL). Some reports have also shown an association of biallelic germline mutations in constitutional mismatch repair-deficiency syndrome genes, MLH1, MSH2, MSH6, and PMS2 with the development of ALL. Isolated hematological malignancies are associated with germline mutations in RUNX1 (familial platelet syndrome with predisposition to acute myelogenous leukemia), CEBPA (familial AML), GATA2 (GATA2-associated syndromes) and DDX41(DDX41 -related myeloid neoplasms). There is a rapidly expanding list of germline mutations associated with increased risks for myeloid malignancies and inherited predisposition to hematologic malignancies may be more common than has been thought. Many different genetic defects associated with the development of leukemia have been described but the common underlying mechanism is a dysfunctional DNA damage response. Recognition of an inherited cause provides a specific molecular diagnosis and helps to guide treatment, understand unique disease features, prognosis and other organ systems that may be involved, and identify others in the family who may be at risk. -
ARTICLES Fibroblast Growth Factors 1, 2, 17, and 19 Are The
0031-3998/07/6103-0267 PEDIATRIC RESEARCH Vol. 61, No. 3, 2007 Copyright © 2007 International Pediatric Research Foundation, Inc. Printed in U.S.A. ARTICLES Fibroblast Growth Factors 1, 2, 17, and 19 Are the Predominant FGF Ligands Expressed in Human Fetal Growth Plate Cartilage PAVEL KREJCI, DEBORAH KRAKOW, PERTCHOUI B. MEKIKIAN, AND WILLIAM R. WILCOX Medical Genetics Institute [P.K., D.K., P.B.M., W.R.W.], Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Obstetrics and Gynecology [D.K.] and Department of Pediatrics [W.R.W.], UCLA School of Medicine, Los Angeles, California 90095 ABSTRACT: Fibroblast growth factors (FGF) regulate bone growth, (G380R) or TD (K650E) mutations (4–6). When expressed at but their expression in human cartilage is unclear. Here, we deter- physiologic levels, FGFR3-G380R required, like its wild-type mined the expression of entire FGF family in human fetal growth counterpart, ligand for activation (7). Similarly, in vitro cul- plate cartilage. Using reverse transcriptase PCR, the transcripts for tivated human TD chondrocytes as well as chondrocytes FGF1, 2, 5, 8–14, 16–19, and 21 were found. However, only FGF1, isolated from Fgfr3-K644M mice had an identical time course 2, 17, and 19 were detectable at the protein level. By immunohisto- of Fgfr3 activation compared with wild-type chondrocytes and chemistry, FGF17 and 19 were uniformly expressed within the showed no receptor activation in the absence of ligand (8,9). growth plate. In contrast, FGF1 was found only in proliferating and hypertrophic chondrocytes whereas FGF2 localized predominantly to Despite the importance of the FGF ligand for activation of the resting and proliferating cartilage. -
Exostoses, Enchondromatosis and Metachondromatosis; Diagnosis and Management
Acta Orthop. Belg., 2016, 82, 102-105 ORIGINAL STUDY Exostoses, enchondromatosis and metachondromatosis; diagnosis and management John MCFARLANE, Tim KNIGHT, Anubha SINHA, Trevor COLE, Nigel KIELY, Rob FREEMAN From the Department of Orthopaedics, Robert Jones Agnes Hunt Hospital, Oswestry, UK We describe a 5 years old girl who presented to the region of long bones and are composed of a carti- multidisciplinary skeletal dysplasia clinic following lage lump outside the bone which may be peduncu- excision of two bony lumps from her fingers. Based on lated or sessile, the knee is the most common clinical examination, radiolographs and histological site (1,10). An isolated exostosis is a common inci- results an initial diagnosis of hereditary multiple dental finding rarely requiring treatment. Disorders exostosis (HME) was made. Four years later she developed further lumps which had the radiological associated with exostoses include HME, Langer- appearance of enchondromas. The appearance of Giedion syndrome, Gardner syndrome and meta- both exostoses and enchondromas suggested a possi- chondromatosis. ble diagnosis of metachondromatosis. Genetic testing Enchondroma are the second most common be- revealed a splice site mutation at the end of exon 11 on nign bone tumour characterised by the formation of the PTPN11 gene, confirming the diagnosis of meta- hyaline cartilage in the medulla of a bone. It occurs chondromatosis. While both single or multiple exosto- most frequently in the hand (60%) and then the feet. ses and enchondromas occur relatively commonly on The typical radiological features are of a well- their own, the appearance of multiple exostoses and defined lucent defect with endosteal scalloping and enchondromas together is rare and should raise the differential diagnosis of metachondromatosis. -
Piggybac Mutagenesis and Exome Sequencing Identify Genetic Driver
Noorani et al. Genome Biology (2020) 21:181 https://doi.org/10.1186/s13059-020-02092-2 RESEARCH Open Access PiggyBac mutagenesis and exome sequencing identify genetic driver landscapes and potential therapeutic targets of EGFR-mutant gliomas Imran Noorani1,2* , Jorge de la Rosa1†, Yoon Ha Choi1,3†, Alexander Strong1, Hannes Ponstingl1, M. S. Vijayabaskar1, Jusung Lee3, Eunmin Lee3, Angela Richard-Londt4, Mathias Friedrich1,5, Federica Furlanetto5, Rocio Fuente1, Ruby Banerjee1, Fengtang Yang1, Frances Law1, Colin Watts2,6, Roland Rad5, George Vassiliou1, Jong Kyoung Kim3, Thomas Santarius2, Sebastian Brandner4 and Allan Bradley1* * Correspondence: [email protected]; [email protected] Abstract †Jorge de la Rosa and Yoonha Choi contributed equally to this work. Background: Glioma is the most common intrinsic brain tumor and also occurs in 1The Wellcome Trust Sanger the spinal cord. Activating EGFR mutations are common in IDH1 wild-type gliomas. Institute, Wellcome Trust Genome However, the cooperative partners of EGFR driving gliomagenesis remain poorly Campus, Hinxton, Cambridgeshire CB10 1SA, UK understood. Full list of author information is Results: We explore EGFR-mutant glioma evolution in conditional mutant mice by available at the end of the article whole-exome sequencing, transposon mutagenesis forward genetic screening, and transcriptomics. We show mutant EGFR is sufficient to initiate gliomagenesis in vivo, both in the brain and spinal cord. We identify significantly recurrent somatic alterations in these gliomas including mutant EGFR amplifications and Sub1, Trp53, and Tead2 loss-of-function mutations. Comprehensive functional characterization of 96 gliomas by genome-wide piggyBac insertional mutagenesis in vivo identifies 281 known and novel EGFR-cooperating driver genes, including Cdkn2a, Nf1, Spred1, and Nav3. -
FGF21 Acts As a Negative Regulator of Bile Acid Synthesis
237 2 Journal of M M Chen, C Hale et al. FGF21 negative regulator of bile 237:2 139–152 Endocrinology acid metabolism RESEARCH FGF21 acts as a negative regulator of bile acid synthesis Michelle M Chen*, Clarence Hale*, Shanaka Stanislaus, Jing Xu and Murielle M Véniant Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California, USA Correspondence should be addressed to M M Véniant: [email protected] *(M M Chen and C Hale contributed equally to this work) Abstract Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid Key Words homeostasis in vivo; its most closely related subfamily member, FGF19, is known to be a f FGF21 critical negative regulator of bile acid synthesis. To delineate whether FGF21 also plays a f Fc-fusion protein functional role in bile acid metabolism, we evaluated the effects of short- and long-term f β-klotho binding exposure to native FGF21 and long-acting FGF21 analogs on hepatic signal transduction, f bile acid gene expression and enterohepatic bile acid levels in primary hepatocytes and in rodent and monkey models. FGF21 acutely induced ERK phosphorylation and inhibited Cyp7A1 mRNA expression in primary hepatocytes and in different rodent models, although less potently than recombinant human FGF19. Long-term administration of FGF21 in mice fed a standard chow diet resulted in a 50–60% decrease in bile acid levels in the liver and small intestines and consequently a 60% reduction of bile acid pool size. In parallel, colonic and fecal bile acid was decreased, whereas fecal cholesterol and fatty acid excretions were elevated. -
FGF Signaling Network in the Gastrointestinal Tract (Review)
163-168 1/6/06 16:12 Page 163 INTERNATIONAL JOURNAL OF ONCOLOGY 29: 163-168, 2006 163 FGF signaling network in the gastrointestinal tract (Review) MASUKO KATOH1 and MASARU KATOH2 1M&M Medical BioInformatics, Hongo 113-0033; 2Genetics and Cell Biology Section, National Cancer Center Research Institute, Tokyo 104-0045, Japan Received March 29, 2006; Accepted May 2, 2006 Abstract. Fibroblast growth factor (FGF) signals are trans- Contents duced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS- 1. Introduction RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/ 2. FGF family GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS~ 3. Regulation of FGF signaling by WNT MAPK signaling cascade is implicated in cell growth and 4. FGF signaling network in the stomach differentiation, the PI3K~AKT signaling cascade in cell 5. FGF signaling network in the colon survival and cell fate determination, and the PI3K~aPKC 6. Clinical application of FGF signaling cascade in cell polarity control. FGF18, FGF20 and 7. Clinical application of FGF signaling inhibitors SPRY4 are potent targets of the canonical WNT signaling 8. Perspectives pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. 1. Introduction Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, Fibroblast growth factor (FGF) family proteins play key roles while recombinant FGF2 protein and FGF4 expression vector in growth and survival of stem cells during embryogenesis, are applicable for therapeutic angiogenesis. Helicobacter tissues regeneration, and carcinogenesis (1-4). -
Targeted Disruption of Shp2 in Chondrocytes Leads to Metachondromatosis with Multiple Cartilaginous Protrusions
ORIGINAL ARTICLE JBMR Targeted Disruption of Shp2 in Chondrocytes Leads to Metachondromatosis With Multiple Cartilaginous Protrusions Harry KW Kim,1,2 Gen‐Sheng Feng,3 Di Chen,4 Philip D King,5 and Nobuhiro Kamiya1,2 1Texas Scottish Rite Hospital for Children, Dallas, TX, USA 2Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA 3Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA 4Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA 5Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA ABSTRACT Metachondromatosis is a benign bone disease predominantly observed in the hands and feet of children or young adults demonstrating two different manifestations: a cartilage‐capped bony outgrowth on the surface of the bone called exostosis and ectopic cartilaginous nodules inside the bone called enchondroma. Recently, it has been reported that loss‐of‐function mutations of the SHP2 gene, which encodes the SHP2 protein tyrosine phosphatase, are associated with metachondromatosis. The purpose of this study was to investigate the role of SHP2 in postnatal cartilage development, which is largely unknown. We disrupted Shp2 during the postnatal stage of mouse development in a chondrocyte‐specific manner using a tamoxifen‐inducible system. We found tumor‐like nodules on the hands and feet within a month after the initial induction. The SHP2‐deficient mice demonstrated an exostosis‐like and enchondroma‐like phenotype in multiple bones of the hands, feet, and ribs as assessed by X‐ray and micro‐computed tomography (CT). Histological assessment revealed the disorganization of the growth plate cartilage, a cartilaginous protrusion from the epiphyseal bone, and ectopic cartilage nodules within the bones, which is consistent with the pathological features of metachondromatosis in humans (ie, both exostosis and enchondroma). -
Prevalence and Incidence of Rare Diseases: Bibliographic Data
Number 1 | January 2019 Prevalence and incidence of rare diseases: Bibliographic data Prevalence, incidence or number of published cases listed by diseases (in alphabetical order) www.orpha.net www.orphadata.org If a range of national data is available, the average is Methodology calculated to estimate the worldwide or European prevalence or incidence. When a range of data sources is available, the most Orphanet carries out a systematic survey of literature in recent data source that meets a certain number of quality order to estimate the prevalence and incidence of rare criteria is favoured (registries, meta-analyses, diseases. This study aims to collect new data regarding population-based studies, large cohorts studies). point prevalence, birth prevalence and incidence, and to update already published data according to new For congenital diseases, the prevalence is estimated, so scientific studies or other available data. that: Prevalence = birth prevalence x (patient life This data is presented in the following reports published expectancy/general population life expectancy). biannually: When only incidence data is documented, the prevalence is estimated when possible, so that : • Prevalence, incidence or number of published cases listed by diseases (in alphabetical order); Prevalence = incidence x disease mean duration. • Diseases listed by decreasing prevalence, incidence When neither prevalence nor incidence data is available, or number of published cases; which is the case for very rare diseases, the number of cases or families documented in the medical literature is Data collection provided. A number of different sources are used : Limitations of the study • Registries (RARECARE, EUROCAT, etc) ; The prevalence and incidence data presented in this report are only estimations and cannot be considered to • National/international health institutes and agencies be absolutely correct. -
FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting
4064 Diabetes Volume 63, December 2014 Qingning Liang,1,2 Ling Zhong,1,2 Jialiang Zhang,1,2 Yu Wang,1,3 Stefan R. Bornstein,4 Chris R. Triggle,5 Hong Ding,5 Karen S.L. Lam,1,2 and Aimin Xu1,2,3 FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting Diabetes 2014;63:4064–4075 | DOI: 10.2337/db14-0541 Hepatic gluconeogenesis is a main source of blood glucose Hepatic gluconeogenesis is tightly controlled by counter- during prolonged fasting and is orchestrated by endocrine regulatory hormones such as glucagon, cortisol, and insulin, and neural pathways. Here we show that the hepatocyte- via regulating the expression of key gluconeogenic enzymes, secreted hormone fibroblast growth factor 21 (FGF21) including glucose 6 phosphatase (G6Pase) and phospho- induces fasting gluconeogenesis via the brain-liver axis. enolpyruvate carboxykinase (PEPCK). Fibroblast growth Prolonged fasting induces activation of the transcrip- factor 21 (FGF21), a metabolic regulator mainly secreted tion factor peroxisome proliferator–activated receptor a a from the liver in response to fasting and starvation under (PPAR ) in the liver and subsequent hepatic produc- – tion of FGF21, which enters into the brain to activate the the control of the nuclear receptor peroxisome proliferator hypothalamic-pituitary-adrenal (HPA) axis for release of activated receptor a (PPARa), plays a critical role in main- corticosterone, thereby stimulating hepatic gluconeogene- taining energy homeostasis and insulin sensitivity in both METABOLISM sis. Fasted FGF21 knockout (KO) mice exhibit severe rodents and nonhuman primates (1–6). A therapeutic dose hypoglycemia and defective hepatic gluconeogenesis due of FGF21 decreased blood glucose in diabetic animals with- to impaired activation of the HPA axis and blunted release out causing hypoglycemia (4). -
Essential Role of Autophagy in Protecting Neonatal Haematopoietic Stem Cells from Oxidative Stress in a P62-Independent Manner
www.nature.com/scientificreports OPEN Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62‑independent manner Naho Nomura1,7,10, Chiaki Ito1,10, Takako Ooshio1,8, Yuko Tadokoro1,2, Susumu Kohno3, Masaya Ueno1,2, Masahiko Kobayashi1,2, Atsuko Kasahara4, Yusuke Takase1,9, Kenta Kurayoshi1, Sha Si1,2, Chiaki Takahashi3, Masaaki Komatsu5, Toru Yanagawa6 & Atsushi Hirao1,2* Autophagy is a cellular degradation system contributing to homeostasis of tissue stem cells including haematopoietic stem cells (HSCs). It plays pleiotropic roles in HSC characteristics throughout life, but its stage‑specifc roles in HSC self‑renewal are unclear. To investigate the efects of Atg5 deletion on stage‑specifc HSC functions, we compared the repopulating capacity of HSCs in Atg5f/f;Vavi-cre mice from postnatal day (P) 0–7 weeks of age. Interestingly, Atg5 defciency led to no remarkable abnormality in the HSC self‑renewal capacity at P0, but signifcant defects at P7, followed by severe defects. Induction of Atg5 deletion at P5 by tamoxifen administration to Atg5f/f;Rosa26-Cre-ERT2 mice resulted in normal haematopoiesis, including the HSC population, until around 1 year, suggesting that Atg5 in the early neonatal period was critical for haematopoiesis in adults. Mitochondrial oxidative stress was increased by Atg5 loss in neonatal HSC/progenitor cells. Although p62 had accumulated in immature bone marrow cells of Atg5f/f;Vavi-cre mice, p62 deletion did not restore defective HSC functions, indicating that Atg5‑dependent haematopoietic regulation in the developmental period was independent of p62. This study proposes a critical role of autophagy in HSC protection against harsh environments in the early neonatal stage, which is essential for healthy long‑term haematopoiesis. -
Whole Exome Sequencing Gene Package Intellectual Disability, Version 9.1, 31-1-2020
Whole Exome Sequencing Gene package Intellectual disability, version 9.1, 31-1-2020 Technical information DNA was enriched using Agilent SureSelect DNA + SureSelect OneSeq 300kb CNV Backbone + Human All Exon V7 capture and paired-end sequenced on the Illumina platform (outsourced). The aim is to obtain 10 Giga base pairs per exome with a mapped fraction of 0.99. The average coverage of the exome is ~50x. Duplicate and non-unique reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA-MEM algorithm (reference: http://bio-bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: http://www.broadinstitute.org/gatk/). The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including OMIM phenotype ID(s) OMIM median depth % covered % covered % covered gene symbol gene ID >10x >20x >30x A2ML1 {Otitis media, susceptibility to}, 166760 610627 66 100 100 96 AARS1 Charcot-Marie-Tooth disease, axonal, type 2N, 613287 601065 63 100 97 90 Epileptic encephalopathy, early infantile, 29, 616339 AASS Hyperlysinemia, -
PDGFB Split FISH Probe Storage Instruction: Store at 4°C in the Dark
PDGFB Split FISH Probe Storage Instruction: Store at 4°C in the dark. Entrez GeneID: 5155 Catalog Number: FS0009 Gene Symbol: PDGFB Regulatory Status: For research use only (RUO) Gene Alias: FLJ12858, PDGF2, SIS, SSV, c-sis Product Description: Labeled FISH probes for identification of gene split using Fluoresecent In Situ Gene Summary: The protein encoded by this gene is a Hybridization Technique. (Technology) member of the platelet-derived growth factor family. The four members of this family are mitogenic factors for Probe 1: cells of mesenchymal origin and are characterized by a Size: motif of eight cysteines. This gene product can exist Fluorophore: either as a homodimer (PDGF-BB) or as a heterodimer Location: PDGFB(Texas Red) with the platelet-derived growth factor alpha polypeptide Approximately 470kb (PDGF-AB), where the dimers are connected by Texas Red disulfide bonds. Mutations in this gene are associated 22q13.1 with meningioma. Reciprocal translocations between Probe 2: chromosomes 22 and 7, at sites where this gene and Size: that for COL1A1 are located, are associated with a Fluorophore: particular type of skin tumor called dermatofibrosarcoma Location: PDGFB(FITC) protuberans resulting from unregulated expression of Approximately 610kb growth factor. Two alternatively spliced transcript FITC variants encoding different isoforms have been identified 22q13.1 for this gene. [provided by RefSeq] Probe Gap: The gap between two probes is approximately 50 kb Source: Genomic DNA Origin: Human Notice: We strongly recommend the customer to use FFPE FISH PreTreatment Kit 1 (Catalog #: KA2375 or KA2691) for the pretreatment of Formalin-Fixed Paraffin-Embedded (FFPE) tissue sections.