1 Newborn Screening Ontario, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;
2 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA;
3 Ottawa Institute of Systems Biology and BMI, University of Ottawa, Ottawa, ON, Canada;
4 Department of Pathology, Boston Children's Hospital, Boston, MA;
5 Department of Haematology, Royal Manchester Children's Hospital, Manchester, United Kingdom;
6 Department of Haematology, Cardiff University School of Medicine, Cardiff, United Kingdom;
7 Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom;
8 Department of Paediatrics, Children's Hospital for Wales, Cardiff, United Kingdom;
9 Department of Child Health, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Children's Hospital for Wales, Cardiff, United Kingdom;
10 Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA;
11 Division of Hematology-Oncology, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medical College, New York, NY;
12 Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada;
13 INSERM UMR773, Université Paris Diderot, Assistance Publique des Hospitaux de Paris, Département de Génétique, Hôpital Xavier Bichat, Paris, France;
14 Department of Pediatric Hematology, Hôpital de la Timone, Marseille, France;
15 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital, Chicago, IL;
16 Paediatric Department, Infectious Diseases and Immunodeficiencies Unit, Centro Hospitalar do Porto, Porto, Portugal;
17 Department of Immunology, Royal Manchester Children's Hospital, Manchester, United Kingdom;
18 Department of Medicine, Hematology-Oncology Section, University of Oklahoma College of Medicine, Oklahoma City, OK;
19 Department of Paediatrics and Medicine, The Hospital for Sick Children, University of Toronto, ON, Canada;
20 Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
21 Bristol Children's Hospital, Bristol, United Kingdom;
22 Department of Pediatric Hemato-Oncology and Stem Cells Transplant, Universitair Ziekenhuis Ghent, Belgium;
23 Department of Chemistry and Biochemistry and Center for Structural and Functional Genomics, Concordia University, Montreal, QC, Canada; and.
24 Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).

Blood. 2014 Oct 30;124(18):2867-71

Authors: Chakraborty PK, Schmitz-Abe K, Kennedy EK, Mamady H, Naas T, Durie D, Campagna DR, Lau A, Sendamarai AK, Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Wynn RF, Laxer RM, Minniti CP, Moppett J, Bordon V, Geraghty M, Joyce PB, Markianos K, Rudner AD, Holcik M, Fleming MD

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.

PMID: 25193871 [PubMed - indexed for MEDLINE]