title: TRNT1 deficiency: clinical, biochemical and molecular genetic features.
abstract: TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs).
  
  
  
  We investigated four patients from two families with infantile-onset cyclical, aseptic febrile episodes with vomiting and diarrhoea, global electrolyte imbalance during these episodes, sideroblastic anaemia, B lymphocyte immunodeficiency, retinitis pigmentosa, hepatosplenomegaly, exocrine pancreatic insufficiency and renal tubulopathy. Other clinical features found in children include sensorineural deafness, cerebellar atrophy, brittle hair, partial villous atrophy and nephrocalcinosis. Whole exome sequencing and bioinformatic filtering were utilised to identify recessive compound heterozygous TRNT1 mutations (missense mutation c.668T>C, p.Ile223Thr and a novel splice mutation c.342+5G>T) segregating with disease in the first family. The second family was found to have a homozygous TRNT1 mutation (c.569G>T), p.Arg190Ile, (previously published). We found normal mitochondrial translation products using passage matched controls and functional perturbation of 3' CCA addition to mitochondrial tRNAs (tRNA(Cys), tRNA(LeuUUR) and tRNA(His)) in fibroblasts from two patients, demonstrating a pathomechanism affecting the CCA addition to mt-tRNAs. Acute management of these patients included transfusion for anaemia, fluid and electrolyte replacement and immunoglobulin therapy. We also describe three-year follow-up findings after treatment by bone marrow transplantation in one patient, with resolution of fever and reversal of the abnormal metabolic profile.
  
  
  
  Our report highlights that TRNT1 mutations cause a spectrum of disease ranging from a childhood-onset complex disease with manifestations in most organs to an adult-onset isolated retinitis pigmentosa presentation. Systematic review of all TRNT1 cases and mutations reported to date revealed a distinctive phenotypic spectrum and metabolic and other investigative findings, which will facilitate rapid clinical recognition of future cases.
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
authors.forename: Yehani
authors.initials: Y
authors.lastname: Wedatilake
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
authors.forename: Rojeen
authors.initials: R
authors.lastname: Niazi
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fassone
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Powell
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pearce
authors.affiliation: UCL Genetics Institute, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Division of Mathematical Biology, National Institute for Medical Research, Mill Hill, London, UK.
authors.forename: José W
authors.initials: JW
authors.lastname: Saldanha
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.|UCL Genetics Institute, London, UK.|Division of Medicine, UCL, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Radiology Department, Great Ormond Street Hospital, London, UK.
authors.forename: W Kling
authors.initials: WK
authors.lastname: Chong
authors.affiliation: Metabolic medicine department, Great Ormond Street Hospital, London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Footitt
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Michal
authors.initials: M
authors.lastname: Minczuk
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK. shamima.rahman@ucl.ac.uk.|Mitochondrial Research Group, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, 30, Guilford Street, London, WC1N 1EH, UK. shamima.rahman@ucl.ac.uk.
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: D000756:Anemia, Sideroblastic / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009713:Nucleotidyltransferases / Q000172:deficiency* / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D012343:RNA, Transfer / Q000235:genetics
chemical_list: D012343:RNA, Transfer; D009713:Nucleotidyltransferases; C000610948:TRNT1 protein, human
keywords: Mitochondrial disease; Protein translation; SIFD; Sideroblastic anaemia; TRNT1; tRNA