DOCSLIB.ORG

Congenital Aplastic Anemia Caused by Mutations in the SBDS Gene: a Rare Presentation of Shwachman-Diamond Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Congenital Aplastic Anemia Caused by Mutations in the SBDS Gene: a Rare Presentation of Shwachman-Diamond Syndrome Congenital Aplastic Anemia Caused by Mutations in the SBDS Gene: A Rare Presentation of Shwachman-Diamond Syndrome Taco W. Kuijpers, MD, PhD*; Eline Nannenberg, MD‡; Marielle Alders, MSc‡; Robbert Bredius, MD, PhD§; and Raoul C. M. Hennekam, MD, PhD*‡ ABSTRACT. Clinical Findings. Aplastic anemia was aly have been observed in the first years of life, with diagnosed at birth for a first child from healthy noncon- subsequent improvement without complications sanguineous parents. The girl had hypoglycemia, which (similar to the pancreatic insufficiency).3 Intermittent normalized within 2 months. Cow milk allergy was sus- neutropenia is the most common hematologic find- pected initially, because of skin lesions and diarrhea, ing in SDS. Hematologic manifestations other than followed by severe growth retardation. Clinical and ra- diologic symptoms gradually became typical for Shwach- neutropenia include anemia, increased fetal hemo- man-Diamond syndrome. Two common mutations in the globin levels, thrombocytopenia, and aplastic ane- -SBDS gene (183-184TA3CT [K62X] and IVS2(258)؉2T3 mia.2,4,5 As with other constitutional BM failure syn C [C84fs]) were found. dromes, there is a tendency toward malignant Results. Bone marrow transplantation from a myeloid transformation. Recombinant human gran- matched unrelated donor was unsuccessful. The genetic ulocyte colony-stimulating factor (G-CSF) has been information from the deceased patient enabled us to used for some SDS subjects with severe neutropenia perform prenatal molecular studies during the subse- but is not recommended because of the risk of acute quent pregnancy, successfully predicting a nonaffected child. myeloid leukemia, although the exact prevalence of Conclusions. This report describes for the first time the disease and its induction by G-CSF are difficult to 2 the hematologic abnormalities of congenital aplastic ane- establish. mia and prolonged neonatal hypoglycemia as the pre- Growth retardation is a typical manifestation. senting symptoms of Shwachman-Diamond syndrome. Weight and length are deficient at birth and remain The finding of common mutations in the presence of below normal with time. Some patients with SDS these symptoms at birth suggests the lack of a clear present with short stature only, rather than malnu- phenotype-genotype relationship in this syndrome. Pe- trition or malabsorption, which suggests an inherent e e diatrics 2004;114: 387– 391. URL: http://www.pediatrics. growth problem. A broad spectrum of skeletal ab- org/cgi/content/full/114/3/e387; aplastic anemia, hematol- ogy, genotype, congenital, bone marrow transplantation. normalities, including metaphyseal dysostosis and epiphyseal dysplasia, has been found to be associ- ated with this syndrome. Additional clinical features ABBREVIATIONS. SDS, Shwachman-Diamond syndrome; CHH, include immune dysfunction, liver disease, renal tu- cartilage/hair hypoplasia; DKC, dyskeratosis congenita; G-CSF, granulocyte colony-stimulating factor; BM, bone marrow; BMT, bular defects, insulin-dependent diabetes mellitus, 6,7 bone marrow transplantation; PCR, polymerase chain reaction. and psychomotor retardation. No unifying pathogenic mechanism has yet been shown to be responsible for SDS, although the ge- hwachman-Diamond syndrome (SDS) (Online netic basis of this rare disease was recently de- Mendelian Inheritance in Man no. 260400) is a scribed.8 Indirect lines of evidence indicate that the Srare autosomal recessive disorder that usually orthologs may function in RNA metabolism. manifests itself in infancy or early childhood. The YLR022c has been clustered with genes encoding disease is extremely heterogeneous, showing a wide RNA-processing enzymes.9 Restriction digestion or variety of abnormalities and symptoms. It is charac- sequencing of polymerase chain reaction (PCR) terized mainly by exocrine pancreatic insufficiency, products from affected individuals showed that short stature, and bone marrow (BM) dysfunction.1–3 ϳ75% of alleles associated with SDS were the result Several studies have shown that, with advancing age, 40% to 60% of patients exhibit pancreatic suffi- of gene conversion, which was confined to a short ciency. Elevated liver enzyme levels and hepatomeg- segment with a maximal size of 240 base pairs. Ap- proximately 90% of affected individuals carry at least 1 converted allele, and 60% carry 2 converted alleles. From *Emma Children’s Hospital and ‡Department of Clinical Genetics, Alleles from affected individuals without conversion Institute for Human Genetics, Academic Medical Center, Amsterdam, Netherlands; and §Leiden University Medical Center, Leiden, Netherlands. mutations had other changes in the coding region of Accepted for publication Apr 8, 2004. SBDS, which led to frameshift and missense chang- DOI: 10.1542/peds.2003-0651-F es.8 We present an unusual case of congenital aplas- Reprint requests to (T.W.K.) Emma Children’s Hospital, Academic Medical tic anemia combined with transient hypoglycemia Center (G8-205), Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: during early infancy with a diagnosis of SDS, which [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- was confirmed by the identification of 2 common emy of Pediatrics. mutations in the SBDS gene. http://www.pediatrics.org/cgi/content/full/114/3/Downloaded from www.aappublications.org/newse387 PEDIATRICS by guest on September Vol. 11425, 2021 No. 3 September 2004 e387 METHODS abnormalities. The 32-year-old white mother and the Hematologic Studies 31-year-old father were both healthy. At the 39th Morphologic analyses demonstrated hypocellular BM in week of gestation, contractions started spontane- smears, which was confirmed with BM biopsies. No excess colla- ously. During the delivery fetal distress developed, gen or signs of fibrosis, disturbed BM stroma development, or prompting a cesarean section. A pale girl with a birth disorganized hematopoiesis was observed. Absolute numbers of weight of 2790 g (10th percentile), length of 38 cm progenitor B cells (CD19ϩ, CD10ϩ, CD24ϩ), T cells (CD2ϩ, CD3ϩ, Ͻ ϩ ϩ Ϫ ϩ ϩ ( 3rd percentile), and occipital-frontal circumfer- CD4 , CD8 ), natural killer cells (CD3 , CD16 , CD56 ), and myeloid cells (CD15ϩ, CD14ϩ, CD16ϩ, CD65ϩ) were determined ence of 35 cm (10th percentile) was born; she expe- with standard fluorescence-activated cell-sorting procedures. Col- rienced respiratory failure, which necessitated artifi- ony-forming units of the erythroid and granulocyte/macrophage cial respiration. The patient had low hemoglobin progenitors were determined in 10- to 14-day semisolid cultures levels and hypoglycemia (Table 1), which were im- and compared with normal age-matched values. mediately corrected. Chest radiographs did not show Histochemical Analyses any defects (in particular, no abnormal ribs, verte- Histochemical and immunophenotypic analyses of the liver brae, or humeri). and muscle were conducted with standard staining procedures, No firm diagnosis was made at that time. with a streptavidin-biotin complex method for paraffin-embedded Kleihauer tests to determine fetomaternal blood loss sections and a 3-step, indirect, immunoperoxidase method, with yielded negative results. The girl was weaned from 3-amino-9-ethylcarbazole as a substrate, for frozen sections. Elec- the ventilator but, for unknown reasons, exhibited tron microscopy was performed with the tissue samples simulta- ϳ neously, with Karnovsky embedding. periods of tachypnea for 8 weeks. Ultrasono- graphic evaluations of the head yielded normal re- Molecular Studies sults. Echocardiography showed nonclosure of the Genomic DNA from peripheral mononuclear cells and fibro- foramen ovale, with moderate left-to-right shunting. blasts from the patient were extracted with standard methods. The The pulmonary artery pressure was 35 mm Hg. SBDS gene was amplified in separate PCRs with primer sets Microbiologic cultures all yielded negative results. identical to those described by Boocock et al,8 with essentially the same genomic PCR conditions as described. Direct sequencing Serologic tests for congenital infections yielded neg- was performed with an ABI PRISM Big Dye terminator v1.1 cycle ative results, as did PCR tests for cytomegalovirus, sequencing kit (Applied Biosystems, Foster City, CA), and PCR parvovirus B19, herpes simplex virus, and Epstein- products were separated in 1% SeaKem (FMC BioProducts, Rock- Barr virus. The patient experienced persistent peri- land, ME) gels, purified with a Qiagen gel extraction kit (Qiagen, Hildena, Germany), and sequenced automatically (ABI3100 se- ods of unexplained hypoglycemia, with transient quencer; Applied Biosystems). lactate acidemia (peak: 5.4 mmol/L). She was exten- sively evaluated for metabolic disorders, in particu- CLINICAL REPORT lar mitochondrial disorders, but no clues were found The proband was the first child of a nonconsan- in a liver biopsy, muscle biopsy, and mitochondrial guineous couple with no family history of congenital DNA analysis. The patient was treated with decreas- TABLE 1. Hematologic and Immunologic Blood Values of the Propositus Birth 2 wk 12 mo* Hematologic findings Hb, mmol/L 2.8† 4.2† 5.5† Hct, L/L 0.23 0.33 Reticulocytes (106 cells/mL) 2.6 8.2 MCV, fL 106 102 Platelets (106 cells/mL) 75 21 50 Leukocytes (106 cells/mL) 1.8 4.2 4.4 Metamyelocytes, % 2 Bands formed, % 1 2 Neutrophils, % 8 8 16 Monocytes, % 5 11 10 Lymphocytes, % 87 80 75 Chemical findings Bilirubin, ␮mol/L 63 166 6 ALAT, IU/L 110 66 ASAT, IU/L
Load more

Recommended publications
  • Identification and Functional Analysis of Novel Genes Associated with Inherited Bone Marrow Failure Syndromes
    Identification and Functional Analysis of Novel Genes Associated with Inherited Bone Marrow Failure Syndromes by Anna Matveev A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Science University of Toronto © Copyright by Anna Matveev 2020 Abstract Identification and Functional Analysis of Novel Genes Associated with Inherited Bone Marrow Failure Syndromes Anna Matveev Master of Science Institute of Medical Science University of Toronto 2020 Inherited bone marrow failure syndromes are multisystem-disorders that affect development of hematopoietic system. One of IBMFSs is Shwachman-Diamond-syndrome and about 80-90% of patients have mutations in the Shwachman-Bodian-Diamond-Syndrome gene. To unravel the genetic cause of the disease in the remaining 10-20% of patients, we performed WES as well as SNP-genotyping in families with SDS-phenotype and no mutations in SBDS. The results showed a region of homozygosity in chromosome 5p-arm DNAJC21 is in this region. Western blotting revealed reduced/null protein in patient. DNAJC21-homolog in yeast has been shown facilitating the release of the Arx1/Alb1 heterodimer from pre-60S.To investigate the cellular functions of DNAJC21 we knocked-down it in HEK293T-cells. We observed a high-level of ROS, which led to reduced cell proliferation. Our data indicate that mutations in DNAJC21 contribute to SDS. We hypothesize that DNAJC21 related ribosomal defects lead to increased levels of ROS therefore altering development and maturation of hematopoietic cells. ii Acknowledgments I would like to take this opportunity to extend my deepest gratitude to everyone who has helped me throughout my degree.
    [Show full text]
  • Is Swachman-Diamond Syndrome a Ribosomopathy?
    Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Of blood, bones, and ribosomes: is Swachman-Diamond syndrome a ribosomopathy? Arlen W. Johnson1,3 and Steve R. Ellis2 1Section of Molecular Genetics and Microbiology, The University of Texas at Austin, Austin Texas 78712, USA; 2Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA Mutations in the human SBDS (Shwachman-Bodian-Di- regulation (Ambekar et al. 2010), and stabilizing the amond syndrome) gene are the most common cause of mitotic spindle (Austin et al. 2008). This has led to the Shwachman-Diamond syndrome, an inherited bone mar- suggestion that SBDS is a multifunctional protein, which row failure syndrome. In this issue of Genes & Develop- in turn has led to considerable discussion about which, ment, Finch and colleagues (pp. 917–929) establish that if any, clinical features of SDS are due to defects in SBDS functions in ribosome synthesis by promoting the ribosome production, and which can be attributed to recycling of eukaryotic initiation factor 6 (eIF6) in a GTP- a role for SBDS in other cellular pathways. The study by dependent manner. This work supports the idea that Finch et al. (2011) in this issue of Genes & Development a ribosomopathy may underlie this syndrome. clearly defines a role of SBDS in ribosome synthesis in mammalian cells. This knowledge represents an impor- tant step in ongoing efforts to equate clinical features of SDS with cellular processes affected by loss-of-function Shwachman-Diamond syndrome (SDS) is an inherited mutations in SBDS.
    [Show full text]
  • Ubiquitin-Proteasome-Rich Cytoplasmic Structures in Neutrophils of Patients with Shwachman-Diamond Syndrome
    Disorders of Phagocytes & Neutropenia Articles and Brief Reports Ubiquitin-proteasome-rich cytoplasmic structures in neutrophils of patients with Shwachman-Diamond syndrome Vittorio Necchi,1,2 Antonella Minelli,1 Patrizia Sommi,1,3 Agostina Vitali,3 Roberta Caruso,4 Daniela Longoni,5 Maria Rita Frau,6 Cristina Nasi,7 Fabiola De Gregorio,8 Marco Zecca,9 Vittorio Ricci,3 Cesare Danesino,1 and Enrico Solcia1 1Department of Human Pathology and Genetics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, Pavia; 2Centro Grandi Strumenti, University of Pavia, Pavia; 3Department of Physiology, University of Pavia, Pavia; 4Department of Pediatric Hematology/Oncology and Transfusion Medicine, IRCCS Pediatric Hospital Bambino Gesù, Rome; 5Department of Pediatrics, University of Milano Bicocca, Monza; 6Azienda Sanitaria ASL Nuoro, Division of Pediatrics, Nuoro; 7Azienda Sanitaria ASL 17, Division of Pediatrics, Savigliano; 8Department of Pediatrics-Federico II University, Napoli; and 9Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy ABSTRACT Funding: this study was Background supported in part by grants from Shwachman–Diamond syndrome is an autosomal recessive disorder in which severe bone mar- the Italian Ministry of Health to row dysfunction causes neutropenia and an increased risk of leukemia. Recently, novel particulate Fondazione IRCCS Policlinico San cytoplasmic structures, rich in ubiquitinated and proteasomal proteins, have been detected in Matteo (RF PSM 2006 401345), epithelial cells and neutrophils from patients with Helicobacter pylori gastritis and several epithelial and from AISS – Associazione Italiana Sindrome di Shwachman, neoplasms. and Regione Lombardia Design and Methods (Progetto SAL-45). Blood neutrophils from 13 cases of Shwachman–Diamond syndrome – ten with and three with- Manuscript received on out SBDS gene mutation – and ten controls were investigated by confocal microscopy and ultra- May 25, 2011.
    [Show full text]
  • Electronic Reprint Crystal Structure of an Iclr Homologue From
    electronic reprint ISSN: 2053-230X journals.iucr.org/f Crystal structure of an IclR homologue from Microbacterium sp. strain HM58-2 Tomonori Akiyama, Yusuke Yamada, Naoki Takaya, Shinsaku Ito, Yasuyuki Sasaki and Shunsuke Yajima Acta Cryst. (2017). F73, 16–23 IUCr Journals CRYSTALLOGRAPHY JOURNALS ONLINE Copyright c International Union of Crystallography Author(s) of this paper may load this reprint on their own web site or institutional repository provided that this cover page is retained. Republication of this article or its storage in electronic databases other than as specified above is not permitted without prior permission in writing from the IUCr. For further information see http://journals.iucr.org/services/authorrights.html Acta Cryst. (2017). F73, 16–23 Akiyama et al. · Isocitrate lyase regulator homologue research communications Crystal structure of an IclR homologue from Microbacterium sp. strain HM58-2 ISSN 2053-230X Tomonori Akiyama,a Yusuke Yamada,b Naoki Takaya,c Shinsaku Ito,a Yasuyuki Sasakia and Shunsuke Yajimaa* aDepartment of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan, bStructural Biology Received 1 November 2016 Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization, c Accepted 2 December 2016 1-1 Oho, Tsukuba 305-0801, Japan, and Department of Environmental and Life Sciences, Tsukuba University, Tennodai, Tsukuba, Japan. *Correspondence e-mail: [email protected] Edited by A. Nakagawa, Osaka University, Japan The bacterial transcription factor IclR (isocitrate lyase regulator) is a member of Keywords: isocitrate lyase regulator; a one-component signal transduction system, which shares the common motif of transcription factor; Microbacterium; hydrazide; a helix–turn–helix (HTH)-type DNA-binding domain (DBD) connected to a one-component system.
    [Show full text]
  • The Human Shwachman-Diamond Syndrome Protein, SBDS, Associates with Ribosomal RNA
    HEMATOPOIESIS The human Shwachman-Diamond syndrome protein, SBDS, associates with ribosomal RNA Karthik A. Ganapathi,1 Karyn M. Austin,1 Chung-Sheng Lee,2 Anusha Dias,2 Maggie M. Malsch,1 Robin Reed,4 and Akiko Shimamura1,3,4 1Department of Pediatric Hematology, Children’s Hospital Boston, 2Department of Cell Biology, Harvard Medical School, 3Department of Pediatric Oncology, Dana-Farber Cancer Institute, 4Harvard Medical School, Boston, MA Shwachman-Diamond syndrome (SDS) is SBDS nucleolar localization is dependent maturation or with decreased levels of an autosomal recessive disorder charac- on active rRNA transcription. Cells from the 60S ribosomal subunit. SBDS forms a terized by bone marrow failure, exocrine patients with SDS or Diamond-Blackfan protein complex with nucleophosmin, a pancreatic dysfunction, and leukemia pre- anemia are hypersensitive to low doses multifunctional protein implicated in ribo- Downloaded from http://ashpublications.org/blood/article-pdf/110/5/1458/1294356/zh801707001458.pdf by guest on 03 May 2021 disposition. Mutations in the SBDS gene of actinomycin D, an inhibitor of rRNA some biogenesis and leukemogenesis. are identified in most patients with SDS. transcription. The addition of wild-type Our studies support the addition of SDS SBDS encodes a highly conserved pro- SBDS complements the actinomycin D to the growing list of human bone marrow tein of unknown function. Data from SBDS hypersensitivity of SDS patient cells. failure syndromes involving the ribo- orthologs suggest that SBDS may play a SBDS migrates together with the 60S some. (Blood. 2007;110:1458-1465) role in ribosome biogenesis or RNA pro- large ribosomal subunit in sucrose gradi- cessing.
    [Show full text]
  • Disruption in Iron Homeostasis and Impaired Activity
    Jain et al. Cell Biosci (2020) 10:105 https://doi.org/10.1186/s13578-020-00468-2 Cell & Bioscience RESEARCH Open Access Disruption in iron homeostasis and impaired activity of iron-sulfur cluster containing proteins in the yeast model of Shwachman-Diamond syndrome Ayushi Jain1, Phubed Nilatawong1,2, Narinrat Mamak3, Laran T. Jensen4 and Amornrat Naranuntarat Jensen1,5,6* Abstract Background: Shwachman-Diamond syndrome (SDS) is a congenital disease that afects the bone marrow, skeletal system, and pancreas. The majority of patients with SDS have mutations in the SBDS gene, involved in ribosome bio- genesis as well as other processes. A Saccharomyces cerevisiae model of SDS, lacking Sdo1p the yeast orthologue of SBDS, was utilized to better understand the molecular pathogenesis in the development of this disease. Results: Deletion of SDO1 resulted in a three-fold over-accumulation of intracellular iron. Phenotypes associated with impaired iron-sulfur (ISC) assembly, up-regulation of the high afnity iron uptake pathway, and reduced activi- ties of ISC containing enzymes aconitase and succinate dehydrogenase, were observed in sdo1∆ yeast. In cells lacking Sdo1p, elevated levels of reactive oxygen species (ROS) and protein oxidation were reduced with iron chelation, using a cell impermeable iron chelator. In addition, the low activity of manganese superoxide dismutase (Sod2p) seen in sdo1∆ cells was improved with iron chelation, consistent with the presence of reactive iron from the ISC assembly pathway. In yeast lacking Sdo1p, the mitochondrial voltage-dependent anion channel (VDAC) Por1p is over- expressed and its deletion limits iron accumulation and increases activity of aconitase and succinate dehydrogenase.
    [Show full text]
  • Shwachman-Diamond Syndrome (SDS) Division of Human Genetics Genes Tested: SBDS
    Shwachman-Diamond syndrome (SDS) Division of Human Genetics Genes Tested: SBDS Molecular Genetics Laboratory Shwachman Diamond syndrome is a severe genetic disorder characterized CLIA#: 36D0656333 by exocrine pancreatic dysfunction, hematologic abnormalities including neutropenia or multi-lineage cytopenia and predisposition towards Phone: (513) 636-4474 myelodysplastic syndrome (MDS) or acute myelogeneous leukemia (AML) Fax: (513) 636-4373 and bone abnormalities. It is the second most common cause of congenital Email: [email protected] exocrine pancreatic insufficiency after cystic fibrosis. The incidence of SDS is approximately 1 in 76,000 births and occurs in all populations. Neonates with SDS are typically asymptomatic. Children with SDS typically Additional information and test requisitions are present within the first year of life with failure to thrive and poor growth due available at: to pancreatic insufficiency in addition to recurrent infections secondary to neutropenia. Malignant transformation, i.e. myelodysplasia and acute www.cincinnatichildrens.org/molecular-genetics myelogenous leukemia, is a significant risk in individuals with SDS. Treatment with granulocyte colony-stimulating factor (G-CSF) reduces the duration and severity of the neutropenia and improves clinical outcome. Hematopoietic stem cell transplantation may be indicated for severe disease. The diagnostic criteria for SDS include: • Pancreatic dysfunction • Neutropenia However, many patients present in an atypical fashion. An expanded set of diagnostic criteria and further information about SDS can be found on the North American SDS Registry website at www.sdsregistry.org. Shwachman Diamond syndrome is inherited as autosomal recessive condition. Biallelic mutations in the Shwachman Diamond gene, SBDS, which maps to 7q11, are found in approximately 80% of individuals who meet the diagnostic criteria for SDS.
    [Show full text]
  • (SBDS) Protein Is a Direct Inhibitor of Protein Phosphatase 2A (PP2A) Activity and Overexpressed in Acute Myeloid Leukaemia
    Leukemia (2020) 34:3393–3397 https://doi.org/10.1038/s41375-020-0814-0 LETTER Acute myeloid leukemia Shwachman–Bodian–Diamond syndrome (SBDS) protein is a direct inhibitor of protein phosphatase 2A (PP2A) activity and overexpressed in acute myeloid leukaemia 1,2 1,2 1,2 3 3 Matthew D. Dun ● Abdul Mannan ● Callum J. Rigby ● Stephen Butler ● Hamish D. Toop ● 4,5 6 1,2,7 1,2 1,2 Dominik Beck ● Patrick Connerty ● Jonathan Sillar ● Richard G. S. Kahl ● Ryan J. Duchatel ● 1,2 1,2 1,2 8 1,2 Zacary Germon ● Sam Faulkner ● Mengna Chi ● David Skerrett-Byrne ● Heather C. Murray ● 1,2 1,2,9 1,2 8 8 Hayley Flanagan ● Juhura G. Almazi ● Hubert Hondermarck ● Brett Nixon ● Geoff De Iuliis ● 2,10 2,10 6 3 1,2,7,11,12 Janis Chamberlain ● Frank Alvaro ● Charles E. de Bock ● Jonathan C. Morris ● Anoop K. Enjeti ● Nicole M. Verrills1,2 Received: 4 July 2019 / Revised: 16 March 2020 / Accepted: 23 March 2020 / Published online: 8 April 2020 © The Author(s) 2020. This article is published with open access To the Editor: FTY720 (reviewed in [2]) and the non-immunosuppressive 1234567890();,: 1234567890();,: chiral-deoxy analogue of FTY720, AAL(S) has a potential The family of serine/threonine phosphatases (PP2A) fre- therapeutic benefit[4, 5]. FTY720 is the most well- quently shows reduced activity in myeloid leukaemias characterised PP2A-activating compound and phosphory- [1, 2]. This is particularly the case in acute myeloid leu- lated by SPHK2 in vivo [6]. FTY720-P acts as a high- kaemias (AML) driven by overexpression or constitutively affinity agonist for four of the five G protein-coupled active c-KIT and FLT3, where PP2A inhibition is required sphingosine-1-phosphate receptors (S1PR), causing recep- for cell transformation which enhances the activation of tor internalisation and increased activity of the JAK2– oncogenic signalling pathways and promotes anti-apoptotic PI3Kγ–PKC signalling axis, a common molecular driver of processes [2–4].
    [Show full text]
  • Mitotic Spindle Destabilization and Genomic Instability in Shwachman-Diamond Syndrome
    Mitotic spindle destabilization and genomic instability in Shwachman-Diamond syndrome Karyn M. Austin, … , David Pellman, Akiko Shimamura J Clin Invest. 2008;118(4):1511-1518. https://doi.org/10.1172/JCI33764. Research Article Hematology Deficiencies in the SBDS gene result in Shwachman-Diamond syndrome (SDS), an inherited bone marrow failure syndrome associated with leukemia predisposition. SBDS encodes a highly conserved protein previously implicated in ribosome biogenesis. Using human primary bone marrow stromal cells (BMSCs), lymphoblasts, and skin fibroblasts, we show that SBDS stabilized the mitotic spindle to prevent genomic instability. SBDS colocalized with the mitotic spindle in control primary BMSCs, lymphoblasts, and skin fibroblasts and bound to purified microtubules. Recombinant SBDS protein stabilized microtubules in vitro. We observed that primary BMSCs and lymphoblasts from SDS patients exhibited an increased incidence of abnormal mitoses. Similarly, depletion of SBDS by siRNA in human skin fibroblasts resulted in increased mitotic abnormalities and aneuploidy that accumulated over time. Treatment of primary BMSCs and lymphoblasts from SDS patients with nocodazole, a microtubule destabilizing agent, led to increased mitotic arrest and apoptosis, consistent with spindle destabilization. Conversely, SDS patient cells were resistant to taxol, a microtubule stabilizing agent. These findings suggest that spindle instability in SDS contributes to bone marrow failure and leukemogenesis. Find the latest version: https://jci.me/33764/pdf Research article Mitotic spindle destabilization and genomic instability in Shwachman-Diamond syndrome Karyn M. Austin,1 Mohan L. Gupta Jr.,2 Scott A. Coats,3 Asmin Tulpule,1 Gustavo Mostoslavsky,4 Alejandro B. Balazs,4 Richard C. Mulligan,4 George Daley,1,2,5 David Pellman,1,2,5 and Akiko Shimamura1,2,3,5 1Department of Pediatric Hematology, Children’s Hospital Boston, Boston, Massachusetts, USA.
    [Show full text]
  • Developmental Dental Disorders
    Developmental Disturbances in Tooth Formaton: Special Needs John J. Sauk DDS, MS Dean & Professor University of Louisville Interprofessional Collaboration &Care First Look! Signaling in Tooth Development Stages of Tooth Development Developmental Disturbances in Tooth Formaton Some genes affecting early tooth development (MSX1, AXIN2,PAX9, LTBP3,EDA) are associated with tooth agenesis and systemic features (cleft palate, colorectal cancer). By contrast, genes involved in enamel (AMELX, ENAM, MMP20, and KLK4) and dentin (DSPP) structures are highly specific for tooth formation. Genes Associated with Tooth Agenesis Non-syndromic oligodontia Mutations in the homeobox gene Oligodontia with mutations MSX1 lead to specific in MSX1 (4p16.1) hypo/oligodontia. Second premolars and third molars are the most Oligodontia with mutations commonly affected teeth in PAX 9 (14q12–q13) Mutations in the transcription factor gene, PAX9, lead to absence of most Oligodontia with mutations permanent molars with or without in AXIN 2 (17q23–24) hypodontia in primary teeth. Mutations in AXIN2 cause tooth Oligodontia with locus agenesis and colorectal cancer mapped to chromosome (OMIM 608615). The patients who 10q11.2 carry the mutation lack 8–27 permanent teeth. Penetrance of colorectal cancer is very high. MSX1 (4p16.1) Congenital agenesis of second premolars at the lower jaw orthopantomogram. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer Severe permanent tooth agenesis (oligodontia) Colorectal neoplasia Dominant inheritance Nonsense mutation Arg656Stop, in the Wnt- signaling regulator AXIN2 Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer Lammi L et al. Am. J. Human Genet. 74 (2004) pp. 1043-1050. Hypodontia as a risk marker for epithelial ovarian cancer Leigh A.
    [Show full text]
  • Shwachman Diamond Syndrome (Sbds) Sequencing
    Lab Dept: Anatomic Pathology Test Name: SHWACHMAN DIAMOND SYNDROME (SBDS) SEQUENCING General Information Lab Order Codes: SBD (Blood or Buccal Swab) Synonyms: Shwachman-Bodian Syndrome; Shwachman-Bodian-Diamond Syndrome; SDS; Pancreatic insufficiency and bone marrow dysfunction; congenital lipomatosis of the pancreas CPT Codes: 81479 – Molecular Pathology Unlisted procedure Test Includes: Analysis is performed by bi-directional sequencing of the coding regions and splice sites of exons 1-5 of the SBDS gene. Mutations found in the first of a family to be tested and is confirmed by repeat analysis using sequencing, restriction fragment analysis, or another appropriate method. Logistics Test Indications: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder that includes pancreatic exocrine insufficiency and hematological abnormalities as consistent features. Other common manifestations include skeletal abnormalities, short stature, liver dysfunction and increased risk of malignancy. Serious infections and acute myeloid leukemia are major causes of mortality and morbidity. The syndrome is caused by the partial, not complete, deficiency of the novel protein encoded by the SBDS gene, thought to be involved in RNA metabolism. In most studies 75-89% of patients with Shwachman-Diamond Syndrome have at least one SBDS gene mutation detected, and usually two. No other gene is known to cause this syndrome. Detection of one mutation is suggestive of the diagnosis, but not definitive. Detection of two mutations is usually definitive but because in this gene two mutations sometimes occur side by side in the same copy (allele) of the gene, follow-up parental testing may be necessary. Reasons for referral: 1. Confirmation of clinical diagnosis.
    [Show full text]
  • A Zebrafish Model for the Shwachman-Diamond Syndrome (SDS)
    0031-3998/08/6304-0348 Vol. 63, No. 4, 2008 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2008 International Pediatric Research Foundation, Inc. ARTICLES A Zebrafish Model for the Shwachman-Diamond Syndrome (SDS) NARAYANAN VENKATASUBRAMANI AND ALAN N. MAYER Department of Pediatrics and Children’s Research Institute, Medical College Of Wisconsin, Milwaukee, WI 53226 ABSTRACT: The Shwachman-Diamond syndrome (SDS) is char- quence identity. However, the pseudogene contains deletions acterized by exocrine pancreatic insufficiency, neutrophil defect, and and nucleotide changes that are predicted to result in protein skeletal abnormalities. The molecular basis for this syndrome was truncation. In the majority of patients with SDS, it appears that recently identified as a defect in a novel nucleolar protein termed the SBDS and SBDSP recombined resulting in unidirectional Shwachman-Bodian-Diamond syndrome (SBDS) protein. Beyond gene conversion from the pseudogene to SBDS (17). This human pathologic descriptions, there are little data addressing the role of SBDS during pancreas and granulocytes development. We gene conversion change is predicted to disrupt the donor hypothesize that sbds gene function is essential for pancreas and splice site of intron 2 and the 8-bp deletion resulting in myeloid development in the zebrafish. By homology searching, we premature truncation of the encoded protein. identified the zebrafish sbds ortholog and then analyzed its expres- The SBDS gene is predicted to encode a novel 250-amino sion by reverse transcriptase-polymerase chain reaction and in situ acid protein. This protein is highly conserved throughout hybridization. We found that the sbds gene is expressed dynamically evolution, and orthologs exist in species from plants, yeast, to during development.
    [Show full text]