DOCSLIB.ORG

Molecular Basis, Diagnosis and Clinical Management Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Molecular Basis, Diagnosis and Clinical Management Of cardio_special issue 2013_biomarin:Hrev_master 05/03/13 09.19 Pagina 2 Cardiogenetics 2013; 3(s1):exxxx3(s1):e2 Molecular basis, diagnosis storage of glycosaminoglycans (GAGs), previ- ously called mucopolysaccharides.1 The defi- Correspondence: Rossella Parini, Department of and clinical management of ciency of one of the enzymes participating in Pediatrics, San Gerardo Hospital, Via Pergolesi mucopolysaccharidoses the GAGs degradation pathway causes progres- 33, 20900 Monza, Italy. sive storage in the lysosomes and consequently Tel. +39.039.2333286 - Fax: +39.039.2334364. E-mail: [email protected] Rossella Parini,1 Francesca Bertola,2 in the cells and results in tissues and organs 3 Pierluigi Russo dysfunction. The damage is both direct or by Key words: mucopolysaccharidoses (MPS), heart, 1UOS Malattie Metaboliche Rare, activation of secondary and tertiary pathways heart and MPS, genetics and MPS. 2 Department of Pediatrics, Fondazione among which a role is played by inflammation. The incidence of MPSs as a group is reported Acknowledgments: RP and PR acknowledge MBBM, Azienda Ospedaliera San between 1:25000 and 1:45000.3 At present 11 dif- patients and their families and Drs. Andrea Gerardo, University of Milano-Bicocca; ferent enzyme deficiencies are involved in Imperatori and Lucia Boffi who collaborated in 2Consortium for Human Molecular the clinical cardiological evaluation of MPSs MPSs producing 7 distinct clinical phenotypes1 Genetics, University of Milano-Bicocca; patients. RP thanks Fondazione Pierfranco e (Table 1).4 Depending on the enzyme deficien- 3UO Department of Cardiology, Azienda Luisa Mariani of Milano for providing financial cy, the catabolism of dermatan sulphate, support for clinical assistance to metabolic Ospedaliera San Gerardo, Monza, Italy heparan sulphate, keratan sulphate, chon- patients and Mrs. Vera Marchetti, the secretary of droitin sulphate, or hyaluronan may be the Metabolic Unit, for her very useful help in impaired, singly or in combination. Diagnosis is managing the patients. suspected clinically and then confirmed by bio- Abstract chemical, enzymatic and molecular tests. For all Contributions: RP, PR, manuscript preparation and first draft; FB, first draft of paragraph What the MPSs types prenatal diagnosis is available are mucopolysaccharidoses for the molecular biol- Mucopolysaccharidoses (MPSs) are a group through enzymatic or molecular analysis. ogist?; PR first draft of paragraph What are of hereditary, monogenic disorders caused by In contrast to a recent past when there was mucopolysaccharidoses for the cardiologist?; RP, lysosomal storage of glycosaminoglycans. Their only palliative treatment for these diseases, other paragraphs and references writing. All incidence as a group is between 1:25,000 and now many specific treatments like hematopoi- authors reviewed the first draft and discussed the 1:45,000. At present 11 different enzyme defi- etic stem cell transplantation (HSCT) in containedonly concepts. ciencies are know to be responsible of 7 similar selected cases (severe MPS I) and enzyme Conflict of interests: RP has received honoraria, but distinct diseases. The diagnosis is suspected replacement therapy (ERT) for MPS I, II, and travel grants and/or research grants from Shire 5 clinically but must be confirmed through bio- VI are available. These treatments are able to HGT, Genzyme Corporation Inc. and BioMarin; FB chemical, enzymatic and molecular analysis. improve the clinical course of the diseaseusehas received travel grants from Genzyme Prenatal diagnosis is feasible for each disease. mainly if started early. This brings along the Corporation Inc.; PR has received travel grants The phenotype worsens with age, due to pro- responsibility for the clinician to recognize from BioMarin. gressive storage, and mainly involves mucosal these diseases at the first signs to allow access tissue, upper airways and lungs, bones and to treatment before a severe damage has been Received for publication: 22 October 2012. Revision received: 1 January 2013. joints, central and peripheral nervous system, established. In this respect pilot studies of Accepted for publication: 11 January 2013. heart, liver, eye and ear. Any type of MPSs, is newborn screening are ongoing.6 In recent characterized by a wide variability of phenotype years, availability of specific treatments, gen- This work is licensed under a Creative Commons ranging from a severe fetal-neonatal disease to eral improvement of palliative medical care Attribution NonCommercial 3.0 License (CC BY- an attenuated form diagnosed in adult individu- and improvement of recognition of mild cases NC 3.0). als. Recently new treatments, like hematopoiet- presenting later in life, have produced a grow- ic stem cell transplantation and enzymatic ing number of adult MPSs patients in relative- ©Copyright R. Parini et al., 2013 Licensee PAGEPress, Italy replacement therapy, became available for many ly good conditions who need to be cared after Cardiogenetics 2013; 3(s1):e2 of these disorders entailing the urgency of early by adult services for metabolic diseases. doi:10.4081/cardiogenetics.2013.s1.e2 diagnosis to allow access to therapies. Thanks to Preparing the right setting for successful tran- therapies these patients have a longer life than sition of these patients from pediatric to adult in the past and this implies that also Non-commercialpalliative service is a difficult task that all the centers for treatments, of which the cardiological ones have MPSs in Europe are dealing with. GAGs. The qualitative analysis is then suggest- a prominent part, must be undertaken diligently. ed. Diagnosis is established by enzyme assay in The cardiologist may face, more frequently than cultured fibroblasts, leukocytes or serum. In expected, with the need to diagnose a patient clinical laboratories residual enzyme activity is with MPS who was not recognized by other spe- Diagnosis of not accurately quantified and is thus not a valid cialists. The echocardiographic features of these mucopolysaccharidoses predictor of disease outcome.1 Conclusive diag- patients are typical and may help in the clinical diagnosis. The future probably deserves to these and prenatal diagnosis nosis is performed with molecular analysis con- disorders other new treatments or combination firming results of enzyme activity and allowing therapies, which might further improve progno- Diagnosis of MPSs is suspected clinically on an early prenatal diagnosis. sis of these diseases. the basis of a number of clinical features (red When a patient is diagnosed with a MPS dis- flags; Table 2),1,4,7,8 but it needs a laboratory con- order, genetic counseling is recommended. firmation. Urine GAGs analysis is a preliminary Genetic counseling can provide the family with diagnostic test. There is a risk of false positive information regarding the genetics, inheri- Introduction and negative results which is less frequent if a tance, and recurrence risks for the specific MPS 24 h urine sample is collected and analyzed. condition in their family. The mucopolysaccharidoses (MPSs) are a There are patients with a normal GAGs urine When the mutations in the family are known, group of monogenic disorders due to lysosomal concentration but an abnormal distribution of prenatal diagnosis can be performed by molecu- [page 2] [Cardiogenetics 2013; 3(s1):e2] cardio_special issue 2013_biomarin:Hrev_master 05/03/13 09.19 Pagina 3 Review lar analysis of tissue obtained by chorionic vil- mented in previous studies and present in of 653 amino acids.11 So far, more than 180 lus or amniocytes sampling. Enzymatic assay is homozygous state or in heterozygous state with mutations have been reported in MPS I often performed as well to guarantee the minor a second known severe mutation and when the patients spread along the entire coding and risk of misdiagnosis. If the mutations are not clinical phenotype is established according to splicing regions without appreciable mutation- completely known the prenatal diagnosis may standardized scoring index of severity. al hot spots. The two most common worldwide be performed with the enzymatic assay alone on Mutations resulting in large alterations of gene mutations are the nonsense p.W402X and chorionic villus sampling or amniocytes.1 sequence, as nonsense mutations or frame- p.Q70X associated to severe phenotype and shifts insertion/deletions, are generally identi- much frequent in North Europe. p.G51D and fied in patients affected by the severe form of p.P496R are specific Italian severe mutations the disease. Missense and splicing mutations whereas p.P533R, spread to Mediterranean What are are sometime compatible with some enzymatic countries, is associated to an intermediate- residual activity and then result in a wide range severe phenotype.12 mucopolysaccharidoses of phenotypes spanning the entire spectrum for the molecular biologist? from severe to attenuated.1 Mucopolysaccharidosis type II The updating of mutations identified is (MPS II) All MPSs have an autosomal recessive trans- available on Human Gene Mutation Database (http://www.hgmd.org). IDS gene maps to chromosome Xq28 and mission with the exception of MPS type II encodes for iduronate-2-sulphatase. Patients (Hunter syndrome) that is X-linked.9 Mucopolysaccharidosis type I are hemizygous males or, very rarely, females Most of MPSs genes have been identified and due to autosomal-X chromosomal transloca- cloned in the 90’s.10 Only HSGNAT gene, respon- (MPS I) tion or non-random X-chromosome inactiva-
Load more

Recommended publications
  • Identification of Novel Genetic Variants Associated with Short Stature in A
    Human Genetics https://doi.org/10.1007/s00439-020-02191-x ORIGINAL INVESTIGATION Identifcation of novel genetic variants associated with short stature in a Baka Pygmies population Matteo Zoccolillo1 · Claudia Moia2 · Sergio Comincini2 · Davide Cittaro3 · Dejan Lazarevic3 · Karen A. Pisani1 · Jan M. Wit4 · Mauro Bozzola5 Received: 1 April 2020 / Accepted: 30 May 2020 © The Author(s) 2020 Abstract Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identifed hundreds of genetic variants having a putative efect on determining adult height in diferent worldwide populations. Theo- retically, a valuable approach to better understand the mechanisms of complex traits as adult height is to study a population exhibiting extreme stature phenotypes, such as African Baka Pygmies. After phenotypic characterization, we sequenced the whole exomes of a cohort of Baka Pygmies and their non-Pygmies Bantu neighbors to highlight genetic variants associated with the reduced stature. Whole exome data analysis revealed 29 single nucleotide polymorphisms (SNPs) signifcantly associated with the reduced height in the Baka group. Among these variants, we focused on SNP rs7629425, located in the 5′-UTR of the Hyaluronidase-2 (HYAL2) gene. The frequency of the alternative allele was signifcantly increased compared to African and non-African populations. In vitro luciferase assay showed signifcant diferences in transcription modulation by rs7629425 C/T alleles. In conclusion, our results suggested that the HYAL2 gene variants may play a role in the etiology of short stature in Baka Pygmies population.
    [Show full text]
  • HYAL2 Antibody (R30915)
    HYAL2 Antibody (R30915) Catalog No. Formulation Size R30915 0.5mg/ml if reconstituted with 0.2ml sterile DI water 100 ug Bulk quote request Availability 1-3 business days Species Reactivity Human, Mouse, Rat. Format Antigen affinity purified Clonality Polyclonal (rabbit origin) Isotype Rabbit IgG Purity Antigen affinity Buffer Lyophilized from 1X PBS with 2.5% BSA and 0.025% sodium azide/thimerosal UniProt Q12891 Applications Western blot : 0.5-1ug/ml Limitations This HYAL2 antibody is available for research use only. Western blot testing of HYAL2 antibody and Lane 1: HeLa; 2: SMMC-7721; 3: COLO320; 4: MCF-7; 5: HT1080 cell lysate Description Hyaluronoglucosaminidase 2, also known as hyaluronidase 2, and LuCa-2, is an enzyme that in humans is encoded by the HYAL2 gene. HYAL2 cDNAs encode a preprotein with an N-terminal signal peptide. Northern blot analysis indicated that the gene was expressed in all human tissues tested except adult brain, and Western blot analysis detected the protein in all mouse tissues examined except adult brain. HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored protein on the cell surface and serves as a receptor for entry into the cell of the jaagsiekte sheep retrovirus (JSRV). The findings of Rai et al.(2001) that HYAL2 is a GPI-anchored protein on the cell surface showed that GFP would likely be cleaved from HYAL2 during GPI addition, leaving HYAL2 on the cell surface and resulting in GFP transit to the lysosome for degradation. Application Notes The stated application concentrations are suggested starting amounts. Titration of the HYAL2 antibody may be required due to differences in protocols and secondary/substrate sensitivity.
    [Show full text]
  • Genetic Deletions in Sputum As Diagnostic Markers for Early Detection of Stage I Non ^ Small Cell Lung Cancer Ruiyun Li,1Nevins W
    Imaging, Diagnosis, Prognosis Genetic Deletions in Sputum as Diagnostic Markers for Early Detection of Stage I Non ^ Small Cell Lung Cancer Ruiyun Li,1Nevins W. Todd,2 Qi Qiu,3 Ta o F a n , 3 Richard Y. Zhao,3 William H. Rodgers,3 Hong-Bin Fang,4 Ruth L. Katz,5 Sanford A. Stass,3 and Feng Jiang3 Abstract Purpose: Analysis of molecular genetic markers in biological fluids has been proposed as a powerful tool for cancer diagnosis. We have characterized in detail the genetic signatures in primary non ^ small cell lung cancer, which provided potential diagnostic biomarkers for lung cancer. The aim of this study was to determine whether the genetic changes can be used as markers in sputum specimen for the early detection of lung cancer. Experimental Design: Genetic aberrations in the genes HYAL2, FHIT,andSFTPC were evalu- ated in paired tumors and sputum samples from 38 patients with stage I non ^ small cell lung cancer and in sputum samples from 36 cancer-free smokers and 28 healthy nonsmokers by using fluorescence in situ hybridization. Results: HYAL2 and FHIT weredeletedin84%and79%tumorsandin45%and40%paired sputum, respectively. SFTPC was deleted exclusively in tumor tissues (71%).There was concor- dance of HYAL2 or FHIT deletions in matched sputum and tumor tissues from lung cancer patients (r =0.82,P =0.04;r =0.84,P = 0.03), suggesting that the genetic changes in sputum might indicate the presence of the same genetic aberrations in lung tumors. Furthermore, abnor- mal cells were found in 76% sputum by detecting combined HYAL2 and FHIT deletions whereas in 47% sputum by cytology, of the cancer cases, implying that detecting the combination of HYAL2 and FHIT deletions had higher sensitivity than that of sputum cytology for lung cancer diagnosis.
    [Show full text]
  • Genome Sequencing Unveils a Regulatory Landscape of Platelet Reactivity
    ARTICLE https://doi.org/10.1038/s41467-021-23470-9 OPEN Genome sequencing unveils a regulatory landscape of platelet reactivity Ali R. Keramati 1,2,124, Ming-Huei Chen3,4,124, Benjamin A. T. Rodriguez3,4,5,124, Lisa R. Yanek 2,6, Arunoday Bhan7, Brady J. Gaynor 8,9, Kathleen Ryan8,9, Jennifer A. Brody 10, Xue Zhong11, Qiang Wei12, NHLBI Trans-Omics for Precision (TOPMed) Consortium*, Kai Kammers13, Kanika Kanchan14, Kruthika Iyer14, Madeline H. Kowalski15, Achilleas N. Pitsillides4,16, L. Adrienne Cupples 4,16, Bingshan Li 12, Thorsten M. Schlaeger7, Alan R. Shuldiner9, Jeffrey R. O’Connell8,9, Ingo Ruczinski17, Braxton D. Mitchell 8,9, ✉ Nauder Faraday2,18, Margaret A. Taub17, Lewis C. Becker1,2, Joshua P. Lewis 8,9,125 , 2,14,125✉ 3,4,125✉ 1234567890():,; Rasika A. Mathias & Andrew D. Johnson Platelet aggregation at the site of atherosclerotic vascular injury is the underlying patho- physiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
    [Show full text]
  • Datasheet: 5030­9954
    Datasheet: 5030­9954 Description: NATIVE BOVINE HYALURONIDASE Name: HYALURONIDASE Format: Purified Product Type: Purified Protein Quantity: 0.5 g Product Details Applications This product has been reported to work in the following applications. This information is derived from testing within our laboratories, peer-reviewed publications or personal communications from the originators. Please refer to references indicated for further information. For general protocol recommendations, please visit www.bio-rad-antibodies.com/protocols. Yes No Not Determined Suggested Dilution ELISA Where this product has not been tested for use in a particular technique this does not necessarily exclude its use in such procedures. Suggested working dilutions are given as a guide only. It is recommended that the user titrates the product for use in their own system using the appropriate negative/positive controls. Target Species Bovine Product Form Purified enzyme from bovine testes - liquid Preservative None present Stabilisers Approx. Protein Total protein concentration 0.2 g/ml Concentrations External Database UniProt: Links Q8SQG8 Related reagents Q5E985 Related reagents Entrez Gene: 281838 HYAL2 Related reagents 515397 HYAL1 Related reagents Product Information Hyaluronidase catalyzes the depolymerization of mucopolysaccharides, hyaluronic acid, and the chondroitin sulfates A and C. The enzyme is widely distributed in animal tissues but is found in great concentrations in the bovine and ovine testes. Molecular Weight MW: 55 kD Activity 315 U/mg protein 1 unit is defined as the amount of enzyme that liberates one micromole of N-acetylglucosamine Page 1 of 2 per minute at 37ºC and pH 4.0. EC 3.2.1.36 Storage Store at -20oC only.
    [Show full text]
  • Oncogenic Transformation by the Jaagsiekte Sheep Retrovirus Envelope Protein
    Oncogene (2007) 26, 789–801 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Oncogenic transformation by the jaagsiekte sheep retrovirus envelope protein S-L Liu1 and AD Miller2 1Department of Microbiology and Immunology, McGill University, Montreal, Canada and 2Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Retroviruses have played profound roles in our under- sarcoma virus, both of which cause tumors in chickens standing of the genetic and molecular basis of cancer. (for a comprehensive review see Rosenberg and Jaagsiekte sheep retrovirus (JSRV) is a simple retrovirus Jolicoeur (1997)). Oncogenic retroviruses are historically that causes contagious lung tumors in sheep, known as classified into acute transforming retroviruses and ovine pulmonary adenocarcinoma (OPA). Intriguingly, nonacute retroviruses. Acute transforming retroviruses OPA resembles pulmonary adenocarcinoma in humans, induce tumors through acquisition and expression of and may provide a model for this frequent human cancer. cellular proto-oncogenes – a process referred to as Distinct from the classical mechanisms of retroviral oncogene capture. These retroviruses induce tumors oncogenesis by insertional activation of or virus capture rapidly, the tumors are of polyclonal origin, and the of host oncogenes, the native envelope (Env) structural viral oncogenes in these viruses are not essential for protein of JSRV is itself the active oncogene. A major virus replication. In fact, acute transforming retro- pathway for Env transformation involves interaction of viruses are often replication-defective (Rous sarcoma the Env cytoplasmic tail with as yet unidentified cellular virus is an exception) because of the loss or disruption of adaptor(s), leading to the activation of PI3K/Akt and essential viral genes during the oncogene capture MAPK signaling cascades.
    [Show full text]
  • Jaagsiekte Sheep Retrovirus (JSRV)
    Jaagsiekte Sheep Retrovirus (JSRV): from virus to lung cancer in sheep Caroline Leroux, Nicolas Girard, Vincent Cottin, Timothy Greenland, Jean-François Mornex, Fabienne Archer To cite this version: Caroline Leroux, Nicolas Girard, Vincent Cottin, Timothy Greenland, Jean-François Mornex, et al.. Jaagsiekte Sheep Retrovirus (JSRV): from virus to lung cancer in sheep. Veterinary Research, BioMed Central, 2007, 38 (2), pp.211-228. 10.1051/vetres:2006060. hal-00902865 HAL Id: hal-00902865 https://hal.archives-ouvertes.fr/hal-00902865 Submitted on 1 Jan 2007 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Copyright Vet. Res. 38 (2007) 211–228 211 c INRA, EDP Sciences, 2007 DOI: 10.1051/vetres:2006060 Review article Jaagsiekte Sheep Retrovirus (JSRV): from virus to lung cancer in sheep Caroline La*,NicolasGa, Vincent Ca,b, Timothy Ga, Jean-François Ma,b, Fabienne Aa a Université de Lyon 1, INRA, UMR754, École Nationale Vétérinaire de Lyon, IFR 128, F-69007, Lyon, France b Centre de référence des maladies orphelines pulmonaires, Hôpital Louis Pradel, Hospices Civils de Lyon, Lyon, France (Received 11 September 2006; accepted 23 November 2006) Abstract – Jaagsiekte Sheep Retrovirus (JSRV) is a betaretrovirus infecting sheep.
    [Show full text]
  • HYAL1 and HYAL2 Inhibit Tumour Growth in Vivo but Not in Vitro
    HYAL1 and HYAL2 Inhibit Tumour Growth In Vivo but Not In Vitro Fuli Wang1., Elvira V. Grigorieva1,2., Jingfeng Li1.¤, Vera N. Senchenko3, Tatiana V. Pavlova1,3, Ekaterina A. Anedchenko3, Anna V. Kudryavtseva3, Alexander Tsimanis4, Debora Angeloni5,6, Michael I. Lerman5, Vladimir I. Kashuba1,7, George Klein1, Eugene R. Zabarovsky1* 1 Microbiology and Tumour Biology Center, Karolinska Institute, Stockholm, Sweden, 2 Institute of Molecular Biology and Biophysics, SD RAMS, Novosibirsk, Russia, 3 Engelhardt Institute of Molecular Biology, Russian Acad. Sciences, Moscow, Russia, 4 Bioactivity Ltd., Rehovot, Israel, 5 Cancer-Causing Genes Section, Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America, 6 Scuola Superiore Sant’Anna and Institute of Clinical Physiology – CNR, Pisa, Italy, 7 Institute of Molecular Biology and Genetics, Ukrainian Academy of Sciences, Kiev, Ukraine Abstract Background: We identified two 3p21.3 regions (LUCA and AP20) as most frequently affected in lung, breast and other carcinomas and reported their fine physical and gene maps. It is becoming increasingly clear that each of these two regions contains several TSGs. Until now TSGs which were isolated from AP20 and LUCA regions (e.g.G21/NPRL2, RASSF1A, RASSF1C, SEMA3B, SEMA3F, RBSP3) were shown to inhibit tumour cell growth both in vitro and in vivo. Methodology/Principal Findings: The effect of expression HYAL1 and HYAL2 was studied by colony formation inhibition, growth curve and cell proliferation tests in vitro and tumour growth assay in vivo. Very modest growth inhibition was detected in vitro in U2020 lung and KRC/Y renal carcinoma cell lines. In the in vivo experiment stably transfected KRC/Y cells expressing HYAL1 or HYAL2 were inoculated into SCID mice (10 and 12 mice respectively).
    [Show full text]
  • Hyaluronidase-2 Regulates Rhoa Signaling, Myofibroblast Contractility, and Other Key Profibrotic Myofibroblast Functions
    The American Journal of Pathology, Vol. 190, No. 6, June 2020 ajp.amjpathol.org EPITHELIAL AND MESENCHYMAL CELL BIOLOGY Hyaluronidase-2 Regulates RhoA Signaling, Myofibroblast Contractility, and Other Key Profibrotic Myofibroblast Functions Adam C. Midgley,* Emma L. Woods,* Robert H. Jenkins,* Charlotte Brown,* Usman Khalid,* Rafael Chavez,* Vincent Hascall,y Robert Steadman,* Aled O. Phillips,* and Soma Meran* From the Wales Kidney Research Unit,* Systems Immunity URI, Division of Infection and Immunity, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom; and the Department of Biomedical Engineering,y Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio Accepted for publication February 7, 2020. Hyaluronidase (HYAL)-2 is a weak, acid-active, hyaluronan-degrading enzyme broadly expressed in somatic tissues. Aberrant HYAL2 expression is implicated in diverse pathology. However, a significant Address correspondence to Soma Meran, M.B.Ch.B., proportion of HYAL2 is enzymatically inactive; thus the mechanisms through which HYAL2 dysregulation fl M.R.C.P., Ph.D., in uences pathobiology are unclear. Recently, nonenzymatic HYAL2 functions have been described, and M.R.C.(Neph.), Wales Kidney nuclear HYAL2 has been shown to influence mRNA splicing to prevent myofibroblast differentiation. Research Unit, Cardiff Univer- Myofibroblasts drive fibrosis, thereby promoting progressive tissue damage and leading to multi- sity School of Medicine, Uni- morbidity. This study identifies a novel HYAL2 cytoplasmic function in myofibroblasts that is unrelated versity Hospital of Wales, to its enzymatic activity. In fibroblasts and myofibroblasts, HYAL2 interacts with the GTPase-signaling Heath Park, Cardiff CF14 4XN, small molecule ras homolog family member A (RhoA). Transforming growth factor beta 1edriven UK.
    [Show full text]
  • Atlas Journal
    Atlas of Genetics and Cytogenetics in Oncology and Haematology Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Portal Teaching X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA Atlas Journal Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 12, Number 4, Jul-Aug 2008 Previous Issue / Next Issue Genes AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)) (10p15.1). Hsueh Kung Lin. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 498-502. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/AKR1C3ID612ch10p15.html CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)) (11q22.3). Yatender Kumar, Vegesna Radha, Ghanshyam Swarup. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 503-518. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CASP1ID145ch11q22.html GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type) (15q21.3). Prakash Radhakrishnan, Pi-Wan Cheng. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 519-524. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/GCNT3ID44105ch15q21.html HYAL2 (Hyaluronoglucosaminidase 2) (3p21.3). Lillian SN Chow, Kwok-Wai Lo. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 525-529. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/HYAL2ID40904ch3p21.html LMO2 (LIM domain only 2 (rhombotin-like 1)) (11p13) - updated. Pieter Van Vlierberghe, Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 530-535. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/RBTN2ID34.html PEBP1 (phosphatidylethanolamine binding protein 1) (12q24.23).
    [Show full text]
  • Chromosome 3P and Breast Cancer
    B.J Hum Jochimsen Genet et(2002) al.: Stetteria 47:453–459 hydrogenophila © Jpn Soc Hum Genet and Springer-Verlag4600/453 2002 MINIREVIEW Qifeng Yang · Goro Yoshimura · Ichiro Mori Takeo Sakurai · Kennichi Kakudo Chromosome 3p and breast cancer Received: April 30, 2002 / Accepted: May 27, 2002 Abstract Solid tumors in humans are now believed to are now believed to develop through a multistep process develop through a multistep process that activates that activates oncogenes and inactivates tumor suppressor oncogenes and inactivates tumor suppressor genes. Loss of genes (Lopez-Otin and Diamandis 1998). Inactivation of a heterozygosity at chromosomes 3p25, 3p22–24, 3p21.3, tumor suppressor gene (TSG) often involves mutation of 3p21.2–21.3, 3p14.2, 3p14.3, and 3p12 has been reported in one allele and loss or replacement of a chromosomal seg- breast cancers. Retinoid acid receptor 2 (3p24), thyroid ment containing another allele. Loss of heterozygosity hormone receptor 1 (3p24.3), Ras association domain fam- (LOH) has been found on chromosomes 1p, 1q, 3p, 6q, 7p, ily 1A (3p21.3), and the fragile histidine triad gene (3p14.2) 11q, 13q, 16q, 17p, 17q, 18p, 18q, and 22q in breast cancer have been considered as tumor suppressor genes (TSGs) for (Smith et al. 1993; Callahan et al. 1992; Sato et al. 1990; breast cancers. Epigenetic change may play an important Hirano et al. 2001a); the commonly deleted regions include role for the inactivation of these TSGs. Screens for pro- 3p, 6q, 7p, 11q, 16q, and 17p (Smith et al. 1993; Hirano et al. moter hypermethylation may be able to identify other TSGs 2001a).
    [Show full text]
  • REPORT Familial Chilblain Lupus, a Monogenic Form of Cutaneous Lupus Erythematosus, Maps to Chromosome 3P
    REPORT Familial Chilblain Lupus, a Monogenic Form of Cutaneous Lupus Erythematosus, Maps to Chromosome 3p Min Ae Lee-Kirsch, Maolian Gong, Herbert Schulz, Franz Ru¨schendorf, Annette Stein, Christiane Pfeiffer, Annalisa Ballarini, Manfred Gahr, Norbert Hubner, and Maja Linne´ Systemic lupus erythematosus is a prototypic autoimmune disease. Apart from rare monogenic deficiencies of complement factors, where lupuslike disease may occur in association with other autoimmune diseases or high susceptibility to bacterial infections, its etiology is multifactorial in nature. Cutaneous findings are a hallmark of the disease and manifest either alone or in association with internal-organ disease. We describe a novel genodermatosis characterized by painful bluish- red inflammatory papular or nodular lesions in acral locations such as fingers, toes, nose, cheeks, and ears. The lesions sometimes appear plaquelike and tend to ulcerate. Manifestation usually begins in early childhood and is precipitated by cold and wet exposure. Apart from arthralgias, there is no evidence for internal-organ disease or an increased sus- ceptibility to infection. Histological findings include a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals show antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins are absent. Thus, the findings are consistent with chilblain lupus, a rare form of cutaneous lupus erythematosus. Investigation of a large German kindred with 18 affected members suggests a highly penetrant trait with autosomal dominant inheritance. By single-nucleotide-polymorphism–based genomewide linkage analysis, the locus was mapped to chromosome 3p. Hap- lotype analysis defined the locus to a 13.8-cM interval with a LOD score of 5.04.
    [Show full text]