title: Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).
abstract: Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.
authors.affiliation: Newborn Screening Ontario, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Pranesh K
authors.initials: PK
authors.lastname: Chakraborty
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA;
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitz-Abe
authors.affiliation: Ottawa Institute of Systems Biology and BMI, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Erin K
authors.initials: EK
authors.lastname: Kennedy
authors.affiliation: Newborn Screening Ontario, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Hapsatou
authors.initials: H
authors.lastname: Mamady
authors.affiliation: Newborn Screening Ontario, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Turaya
authors.initials: T
authors.lastname: Naas
authors.affiliation: Newborn Screening Ontario, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Danielle
authors.initials: D
authors.lastname: Durie
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA;
authors.forename: Dean R
authors.initials: DR
authors.lastname: Campagna
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA;
authors.forename: Ashley
authors.initials: A
authors.lastname: Lau
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA;
authors.forename: Anoop K
authors.initials: AK
authors.lastname: Sendamarai
authors.affiliation: Department of Haematology, Royal Manchester Children's Hospital, Manchester, United Kingdom;
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wiseman
authors.affiliation: Department of Haematology, Cardiff University School of Medicine, Cardiff, United Kingdom;
authors.forename: Alison
authors.initials: A
authors.lastname: May
authors.affiliation: Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom;
authors.forename: Stephen
authors.initials: S
authors.lastname: Jolles
authors.affiliation: Department of Paediatrics, Children's Hospital for Wales, Cardiff, United Kingdom;
authors.forename: Philip
authors.initials: P
authors.lastname: Connor
authors.affiliation: Department of Child Health, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Children's Hospital for Wales, Cardiff, United Kingdom;
authors.forename: Colin
authors.initials: C
authors.lastname: Powell
authors.affiliation: Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA;
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Heeney
authors.affiliation: Division of Hematology-Oncology, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medical College, New York, NY;
authors.forename: Patricia-Jane
authors.initials: PJ
authors.lastname: Giardina
authors.affiliation: Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klaassen
authors.affiliation: INSERM UMR773, Université Paris Diderot, Assistance Publique des Hospitaux de Paris, Département de Génétique, Hôpital Xavier Bichat, Paris, France;
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.affiliation: Department of Pediatric Hematology, Hôpital de la Timone, Marseille, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thuret
authors.affiliation: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital, Chicago, IL;
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Thompson
authors.affiliation: Paediatric Department, Infectious Diseases and Immunodeficiencies Unit, Centro Hospitalar do Porto, Porto, Portugal;
authors.forename: Laura
authors.initials: L
authors.lastname: Marques
authors.affiliation: Department of Immunology, Royal Manchester Children's Hospital, Manchester, United Kingdom;
authors.forename: Stephen
authors.initials: S
authors.lastname: Hughes
authors.affiliation: Department of Haematology, Royal Manchester Children's Hospital, Manchester, United Kingdom;
authors.forename: Denise K
authors.initials: DK
authors.lastname: Bonney
authors.affiliation: Department of Medicine, Hematology-Oncology Section, University of Oklahoma College of Medicine, Oklahoma City, OK;
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Bottomley
authors.affiliation: Department of Haematology, Royal Manchester Children's Hospital, Manchester, United Kingdom;
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
authors.affiliation: Department of Paediatrics and Medicine, The Hospital for Sick Children, University of Toronto, ON, Canada;
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Laxer
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Caterina P
authors.initials: CP
authors.lastname: Minniti
authors.affiliation: Bristol Children's Hospital, Bristol, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: Moppett
authors.affiliation: Department of Pediatric Hemato-Oncology and Stem Cells Transplant, Universitair Ziekenhuis Ghent, Belgium;
authors.forename: Victoria
authors.initials: V
authors.lastname: Bordon
authors.affiliation: Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Michael
authors.initials: M
authors.lastname: Geraghty
authors.affiliation: Department of Chemistry and Biochemistry and Center for Structural and Functional Genomics, Concordia University, Montreal, QC, Canada; and.
authors.forename: Paul B M
authors.initials: PB
authors.lastname: Joyce
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA;
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Markianos
authors.affiliation: Ottawa Institute of Systems Biology and BMI, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Adam D
authors.initials: AD
authors.lastname: Rudner
authors.affiliation: Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA;
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
mesh_terms: D000483:Alleles; D000756:Anemia, Sideroblastic / Q000150:complications / Q000151:congenital* / Q000201:enzymology / Q000235:genetics*; D002658:Developmental Disabilities / Q000150:complications* / Q000235:genetics; D005334:Fever / Q000150:complications* / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D012316:RNA Nucleotidyltransferases / Q000235:genetics*
chemical_list: D012316:RNA Nucleotidyltransferases; C023198:tRNA nucleotidyltransferase